UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 22-AUGUST-2015 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Rotenone. Human Health Assessment Scoping Document in Support of 

Registration Review. 

OP Barcodc: 0427109 

Registration No.: NIA 

PC Code: 071003 

Decision No.: 503939 

Petition No.: NIA 

Risk Assessment Type: NIA 

TXR No.: NIA 

Regulatory Action: Registration Review Scoping Document 

Case No.: NIA 

MRIO No.: NIA 

FROM: 

CAS No.: 83-79-4 

40 CFR: NIA 

B

Nancy 

Su

ri

mitr

dgett 

a 

McCarroll

B

Bobowiec

ose Biswas

, Toxicolog

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o

Chemis

logist 

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. /V~ fJ, c..l 

Risk Assessment Branch VI (RAB6) I 

Health Effects Division (I-JED) (7509P) 

THROUGH: Donna Davis, Acting Branch Chief 

Risk Assessment Branch VI 

Health Effects Division (7509P) 

TO: Kelly Ballard, Chemical Review Manager 

Risk Management and Implementation Branch I 

Pesticide Re-Evaluation Division (PRO) (7508P) 

\ 

Attached is HED's human health risk assessment scoping document for rotenone to support 

Registration Review. The most recent quantitative human health risk assessment was conducted 

in 2006 (Memo, C. Smith, 28-JUNE-2006; 0328478). 

Page I of 19 
Rotenone Registration Review I luman Health Assessment Scoping Document 

Table of Contents 

Executive Sum1nary ........................ .......................................................................................... ...... 3 

1.0 Introduction .............. ............... ............. ........ ......... ........... ............ ....... .............. ...... ................. 4 

2.0 Hazard Characterization/Assessment.. ..................................................................................... 5 

3.0 Residue Chemistry and Dietary Exposure ........ ............ ........................................................... 6 

4.0 Residential Exposure ........................... ................ ................ .................. .......... ... .... ... .............. 7 

5.0 Aggregate Risk Assessment. .................................................................................................... 7 

6.0 Occupational Exposure .................................................... .... .................. ... ............................... 8 

7.0 Public Health and Pesticide Epidemiology Data .... ... ........ ................... .......... .......... ............... 8 

8.0 Tolerance Assessment and International Harmonization ........................................................ 9 

9 .0 Environmental Justice ................................................................................. ............................. 9 

I 0.0 Cumulati ve ..... .... ................... ........ ..... ........ .............................................................. ....... ... .... 9 

I 1.0 Hu1nan Studies ..................... .... .............................................................................................. 9 

12.0 References ............................................................................................................................ 10 

Attachment I: Chemical Identity and Dietary Tables .. ............ ....... .... ....... .............. ............. ....... 11 

Attachment 2: Rotenone Acute, Subchronic, and Chronic Toxicity Profile ................................ 13 

Attachment 3: Toxicological Doses and Endpoints for Rotenone ............................................... 18 

Attachment 4: Summary of Registered Uses for Rotcnone ... .... .... .... ....... .................... ............... 19 

Page 2 of 19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Executive Summary 

HED has prepared a scoping document to support Registration Review of rotenone: a restricted 

use piscicidal chemical, applied directly to water by helicopters, closed system aspirators, boats, 

and handheld equipment to manage fish populations in lakes, ponds, reservoirs, rivers, and 

streams. Rotenone is formulated as a suspension-concentrate (SC) and wettable powder (WP) 

in several end-use products ranging from 5 % to 7.4% active ingredient (ai) [2 pounds (lbs) 

ail gallon; EPA Reg. No. 264-831]. Jn April of 2000 detailed standard operating procedures 

(SOPs) in the form of a management manual entitled ROTENONE USE IN FISHERIES 

MANAGEMENT: Administrative and Technical Guidelines Manual, was produced by the 

American Fisheries Society. Registered rotenone labels should have language to direct users to 

this manual, which includes the most up-to-date restrictions, application methods and personal 

protection equipment (PPE) requirements. The manual was updated in 20 I 0. 

HED has considered all available data and human health risk assessments for rotenone with 

respect to its toxicity, exposure, and usage databases, and the most updated Agency science 

policy and risk assessment methodologies to determine the scope of work necessary to support 

Registration Review. 

The toxicity database for rotenone is not complete as required by the 2007 revised 40 CFR 

Toxicology Data Requirements; however the data will not be required for registration review 

unless there are changes in the limited rotenone use pattern. The toxicological data deficiencies 

identified in the data call in (DCI) remain in reserve at this point and include the fo llowing; 

subchronic inhalation neurotoxicity study, an acute neurotoxicity study as well as a chronic dog, 

developmental toxicity in non-rodents, a 21 -day dermal, a dermal penetration, a guideline 

metabolism, and an immunotoxicity study. In 2006 an additional I OX (level of concern (LOC) 

=1,000) was retained for all risk assessments to account for database uncertainty. Rotenone is 

classified as Toxicity Category I for oral and inhalation routes of exposure and Toxicity 

Category IV via the dermal route of exposure. Rotenone is not an eye or skin irritant nor is it a 

skin sensitizer. The carcinogenic classification for rotenone is "not likely to be carcinogenic in 

humans," based on the lack of evidence of carcinogenicity in rats and mice. 

The dietary exposure and residue chemistry databases are considered complete. Non-aquatic 

rotenone uses were terminated in spring of 2006 and therefore, dietary (food) exposure 

assessment is not required. Environmental Fate and Effects Division (EFED) provided HED 

with an acute estimated drinking water concentration (EDWC) of 200 ppb for surface water (R. 

David Jones, 0307383, 5110/2006) based on the solubility of rotenone in water. In 2006, an 

acute and chronic dietary exposure assessment was performed for rotenone considering 

exposures from drinking water only (T. Goodlow, D328785, 617/2006). Exposure from the 

water was below the HED's level of concern (< I 00%). The rotenone fisheries management 

guideline manual has mandatory restrictions and SOPs to prevent consumption of treated fish. 

Rotenone is exempt from the need to establish tolerances. The Food Quality Protection Act 

(FQPA) of 1996 does not apply to rotenone and therefore, HED does not need to aggregate 

pesticide exposures and risk from other sources of exposure (drinking water and residential 

exposures). However, exposure from various routes and pathways may be combined in 

registration review if the toxicological effects are the same and exposure is expected to co-occur. 

There are no proposed or current residential uses for rotenone and therefore, a residential handler 

exposure assessment is not required for registration review at this time. However, residential 

Page 3of 19 
Rotenone Registration Review Human Health Assessment Scoping Document 

exposure is possible through swimming and ingestion of previously treated water. In the 2006 

risk estimates for short-tem1 post-application combined dermal and oral exposure to children 

(ages from I< 2 years old) from swimming in previously treated water were of concern (margins 

of exposure (MOE)s < 1,000) at day 0 after treatment. The calculated concentration level for 

incidental oral ingestion at which MOES exceeded 1,000 was 90 parts per billion (ppb) (0.24 lb 

ai/A ft). From this calculation, HED recommended swimming prohibition for at least three days 

after the maximum application rate (250 ppb/0.68 lb ai/A ft). There have been updates to the 

swimming exposure model since the 2006 risk assessment and the American fisheries rotenone 

manual. These updated exposure assumptions will be need to be incorporated as part of 

Registration Revi ew. The Registration Review process will also include consideration for 

rotenone bystander spray drift and volatilization assessments. 

The occupational exposure database is adequate to support the Registration Review process for 

rotenonc. In the 2006 risk assessment, there were occupational handler risk estimates of concern 

(MO Es < LOC) for scenarios that involved mixing/loading of liquid and wettable powder 

rotenone formulations and for mixing/loading/applying rotenone using boat aspirators and 

backpack sprayers despite maximum mitigation possibilities such as respirators and closed 

systems for mixing and loading. HED expects minimal occupational post-application exposure 

from the piscicidal use of rotenone. As a result, no quantitative occupational post-application 

assessment is expected, however an updated occupational handler assessment to reflect all 

registered uses, maximum application rates, and most up-to-date exposure policies and 

toxicological points of departure (PO Os) will be required for Registration Review 

1.0 Introduction 

Rotenone, or (6R, 6aS, l 2aS)-I ,2,6,6a, 12, I 2a-hexahydro-2-isopropenyl-8,9- dimethoxychromenyl[3,4- bfuro[2,3-h]chromen-6-one, is a naturally occurring compound that is present 

in a number of plants. This botanical pesticide derived from the roots of Derr is spp., 

lonchocatpus spp., and Tephrosia spp., found primarily in Malaysia, South America, and East 

Africa, is registered by EPA for piscicidal (fish kill) uses. The last human health risk assessment 

was in 2006 and was the Final HED Chapter of the Reregistration Eligibility Decision Document 

(RED) (Memo, C. Smith, 28-JUNE-2006; D328478). In addition to the RED, in 2014 there was 

a Section 18 emergency use submitted for an unregistered rotenone product (Memo, M. 

Sahafeyan. 07-AUG-2014; 0421308). 

Rotenone is applied directly to water to manage fish populations in lakes, ponds, reservoirs, 

rivers, and streams. Rotenone products are classified as restricted use pesticides due to high 

acute inhalation, acute oral, and aquatic toxicity. The chemical can rapidly degrade in soil, 

water, and by sunlight, usually within 2-5 days but may persist for as long as 6 months in colder 

weather. Registered formulations of rotenone include liquid and wettable powder formulations 

with applications made by helicopters and boats in lakes, reservoirs, and ponds; with direct 

metering into moving water such as streams; and with hand-held equipment such as backpack 

sprayers in difficult-to-reach aquatic areas. Current PPE for the various handler scenarios 

include, coveralls and gloves over baseline dermal protection, PFS and PF 10 respirators, and 

semi-closed systems for diluting concentrate. Reentry is restricted unti I concentration levels fall 

below 90 ppb. The application methods, PPE requirements, reentry restriction SOPs are 

discussed in detail in the ROTENONE USE JN FISHERIES MANAGEMENT: Administrative 

and Technical Guidelines Manual produced by the American Fisheries Society. There are no 

Page 4 of 19 
Rotenonc Registration Review Human Health Assessment Scoping Document 

tolerances established for rotenone because fish kill harvesting practices, restrictions on 

concentrations prior to restocking are in place to prevent consumption of treated fish. 

2.0 Hazard Characterization/ Assessment 

Since the RED document was finalized (Smith et al., 2006), no new studies have been received 

for rotenone. Therefore, the toxicology database remains incomplete; however, because of the 

limited use pattern and accompanying use manual for rotenone, the missing studies remain in 

reserve but do not prevent registration review. The reserve studies include a chronic dog, 

developmental toxicity (non-rodents), dermal penetration, a 21-day dermal toxicity study, a 

guideline metabolism study, as well as acute neurotoxicity study. Similarly, an inhalation 

neurotoxicity study with rotenone, which was the subject of a Data Call In (DCI) (GDCI071003-20980), has never been satisfied and a submitted data waiver was denied (Locke, 2004). 

In accordance with the revised 2007 40 CFR Part 158 Toxicology Data Requirements, an 

immunotoxicity study is now required for food and non-food use pesticides, however due to the 

limited use pattern, an additional DCI for this study is not required at this time. A toxicology 

database 1 OX uncertainty factor (UF) is still in place for the various points of departure (PO Os) 

selected for the dietary (water only), residential and occupational risk assessments. 

A definitive target organ has not been identified for rotenone but numerous published literature 

studies within the past I 0 years indicate that rotenone, via intravenous or subcutaneous routes, 

induces behavioral, biochemical, and neuropathological effects. While neither route of exposure 

is relevant to the risk assessment, the intravenous route may mimic inhalation exposure, which is 

a route of concern with rotenone. The only available inhalation toxicity study is an acute LCso in 

the rat (Category I). However, none of the presented studies, which are suitable for risk 

assessment purposes, are adequate to address the neurotoxicity concerns or the inhalation route 

of exposure. 

Minimal systemic toxicity has been observed in the database and the most common effect in 

subchronic or chronic rat, dog, mouse, and/or hamster oral studies, is decreased body weight 

and/or body weight gain. Rats and dogs appear to be equally sensitive and both are more 

sensitive than mice or hamsters; females appear to be more sensitive than males to effects on 

body weight. No conclusions can be reached for either dermal or inhalation routes of 

administration since route specific data is not avai lable for these routes of exposure. In the 

developmental studies, maternal toxicity occurred either at lower doses (rats) or at an equivalent 

dose in mouse maternal animals and the pups; no study was available on a non-rodent species. 

In a two-generation reproductive toxicity study (rat), adult and offspring toxicity were observed 

at doses greater than 3.0 mg/kg/day. The main effect in both parental animals and pups was 

decreased body weight and body weight gain. At this time, no quantitative or qualitative 

evidence supports increased susceptibility ofrat or mouse fetuses or rat offspring. rt is currently 

unknown; however, whether in utero exposure to rotenone in the developing rabbit results in 

toxicity below or at the same dose resulting in maternal toxicity. Likewise, post-natal growth 

and survival is unknown for the developing rabbit. 

No evidence for carcinogenicity was seen in mice or rats and it is not mutagenic in vitro or in 

vivo. Therefore, rotenone is classified as Group E (evidence of non-carcinogenicity for humans) 

(Memo, R. Gardner, 05-0CT-1988, TXR0052673). 

Page 5of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

In acute oral and inhalation studies, rotenone is classified as Category I, severely toxic but is not 

toxic dermally (Category IV) or causes eye or dermal irritation (Category IV), and it is also not a 

dermal sensitizer. 

An appropriate acute endpoint for the general population, including infants and children, was not 

identified in the available toxicity studies. The acute dietary (drinking water only) risk estimate 

calculated for females 13-49 years of age is based on a NOAEL of 15 mg/kg/day from the mouse 

developmental study. The chronic dietary (drinking water only) risk estimated was derived from 

the NOAEL of 0.375 mg/kg/day in the chronic/carcinogenicity rat study. The short- and 

intermediate-term (non-cancer) dermal occupational and residential risk assessment for rotenone 

is based on a NOA EL of 0.5 mg/kg/day from a reproduction study with a dermal absorption 

factor of 10 percent selected. Long-term exposure to rotenone is not expected for current 

registered uses. The dermal, inhalation, and incidental oral margins of exposure were combined 

for the rotenone risk assessment because the endpoints are based on the same toxicological 

effects. Effects were seen in both male and females so the body weight of an average adult (i.e., 

80 kg) was used to estimate exposure. Because of a significant gaps in the toxicology database 

an additional l OX UF has been applied to the various points of departure (PODs) selected. 

Conclusions for Hazard Assessment: The toxicity database for rotenone is not complete; 

however, data gaps are being he ld in reserve and do not preclude registration review. As part of 

Registration Review. all endpoints used for rotenone risk assessment will be updated to reflect 

current HED policy. Until the missing data are presented to HED, the additional 1 OX UF will be 

applied to a ll PODs. 

3.0 Residue Chemistry and Dietary Exposure 

The last residue chemistry review was completed for the RED in 2006 (Memo, C. Smith, 28-

JUN E-2006; 0328478). Residue chemistry data deficiencies cited in that memo have not been 

addressed for rotenonc because all food uses have since been cancelled. Therefore, at present 

time, there are no outstanding deficiencies provided there is no request for a food use. There are 

no tolerances established for rotenone because fish kill harvesting practices, restrictions on 

concentrations prior to restocking are in place to prevent consumption of treated fish. 

The fate and transport properties of rotenone in the environment are not well understood. 

Rotcnone historically has been characterized as immobile, non-persistent, and does not appear to 

bioaccumulate. This characteri zation is true in some circwnstances (Memo, R. David Jones, 05-

MA Y-2006, 0307383). Rotenone does degrade rapidly by aqueous photolysis (the photolysis 

half-life is less than one day) on warm sunny days in clear water and moderately at temperatures 

of25°C (half-lives of 12.6 days at a pH of 5 and 2 days at a pH of 9). However, aquatic field 

studies show that rotenone can persist in cold water at sufficient concentrations to cause fish 

mortality for at least 25 days, even in alkaline conditions. 

EFED provided HED with an estimated drinking water concentration (EDWC) of200 ppb for 

surface water (Memo, R. David Jones, 05-MA Y-2006, 0307383) based on the solubility of 

rotenone in water. It is also worth noting that the maximum application rate assessed 2006 250 

ppb exceeds the solubility of rotenone. The suspended or emulsified rotenone will be less 

available for metabolism or hydrolysis than that in the dissolved phase. In 2006 an acute dietary 

exposure assessment was performed for rotenone considering exposures from drinking water 

only (T. Goodlow, 0328785, 6/7/2006) using the Dietary Exposure Evaluation Model (DEEMFCIDTM, Version 2.03). The acute dietary exposure from drinking water concentrations were 

Page 6of19 
Rotenone Regish·ation Review Human Health Assessment Scoping Document 

below HED's level of concern (< 100 % acute PAD) for all population subgroups. Using the 

drinking water level of comparison (DWLOC) approach, HED determined that chronic drinking 

water exposures greater than 40 ppb could pose a potential risk of concern (> I 00% cRfD) to the 

most highly exposed population subgroups, infants and children. An updated dietary assessment 

(water only) is required as a part of the registration review. 

4.0 Residential Exposure 

There are no registered or proposed rotenone products that allow for residential use. Rotenone is 

a restricted use (RU) pesticide; therefore, a quantitative residential handler exposure assessment 

is not expected. However, there is the potential for exposure to individuals in an environment 

that has been previously treated with rotenone. ln 2006, HED completed an assessment for 

residential post-application exposure from recreational swimming in rotenone-treated waters. 

The calculated post-application swimming short-term dermal and incidental ingestion risk 

estimates were of concern (MO Es < 1,000) for children (ages 1 to < 2 years old). Acceptable 

combined risk estimates were not of concern at 90 ppb concentration. This back calculation lead 

to a prohibition of swimming for at least 2 days after completion of a 200 ppb (0.54 lb ail A ft) 

rotenone application and at least 3 days after completion of a 250 ppb (0.68 lb ai/A ft) rotenone. 

The aquatic use SOP swimming model has since been updated and a new swimming assessment 

will be necessary for Registration Review. 

Spray Drift and Volatilization: Residential bystander exposures resulting from off-site transport 

(e.g., spray drift or volatilization) may occur as a result of applications ofrotenone. The 

potential for spray drift will be quantitatively evaluated for each pesticide during the Registration 

Review process that ensures that all uses of pesticides will be considered concurrently. The 

approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk 

Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 

I: Consideration of Spray Drift. This document outlines the quantification of indirect nonoccupational exposure to drift. In terms of volatilization, the agency has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-20 14-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analyses are required for specific chemicals. 

Conclusions (or Residential Assessment: The residential exposure database is considered 

complete. There are no proposed or current registrations for products containing rotenone that 

allow residenti al use. Therefore, residenti al handler exposure assessments will not be needed 

during Registration Review. Updated residential post-application risk assessments will be 

required, however due to the updated 2015 aquatic SOP and if significant changes are made to 

the PODs and/or UFs. The need for spray drift and volatili zation risk assessment for rotenone 

will be considered during Registration Review. 

5.0 Aggregate Risk Assessment 

In accordance with the Food Quality Protection Act (FQPA) of 1996, for chemicals having 

tolerances in food, HED must consider and aggregate pesticide exposures and risks from three 

major sources: food, drinking water, and residential exposures (oral, dermal, and inhalation). All 

uses of rotenone on food crops were cancelled and thus, the requirements of FQPA are not 

applicable, however, based on the currentl y registered uses for rotenone, a dietary (drinking 

Page 7of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

water only) assessment will be conducted. Therefore, HED will consider the aggregate 

exposures and risks of the dietary (drinking water only) as well as the residential post-application 

exposures, as appropriate, during Registration Review. 

Conclusions (or Aggregate Assessment: During Registration review HED will consider the need 

for an aggregate assessment combining the drinking water (dietary) and nonoccupational 

exposures as appropriate. 

6.0 Occupational Exposure 

Occupational handlers are anticipated to have short- and intermediate-term dermal and inhalation 

exposures. Risk estimates of concern were identified for occupational handlers in the previous 

2006 risk assessment. Occupational long-term exposures to rotenone are not expected for 

rotenone piscicide uses. In the 2006 risk assessment, there were combined dermal and inhalation 

risk estimates of concern (MO Es< 1,000) for both liquid formulations and wettable powder 

formulations for mixing and loading for boat applications even with maximum risk mitigation of 

a closed system. Many of the mixer/loader/applicator scenarios for lake and pond sites also 

exceeded HED's level of concern even at maximum risk mitigation using closed systems for 

mixing and loading. Rotenone application to moving water (i.e., streams) using below water 

surface drip bars resulted in no risk estimates of concern with assumptions based on no contact 

with rotenone once loaded. In support of Registration Review, an updated occupational 

exposure assessment for rotenone will be conducted for all of the formulations types and possible 

exposure scenarios. New risk estimates will reflect updates to American Fisheries Rotenone 

Manual, HED's SOPs along with policy changes for body weight assumptions, available 

chemical specific data, and changes to PODs or UF/SFs. 

An updated occupational dermal post-application assessment is not required during Registration 

Review. It is unlikely for occupational workers to come into contact with previously treated 

water except for water sample and dead fish collection. HED does not have data to assess these 

post-application activities, which are assumed to be negligible when compared to the 

occupational handler exposure scenarios. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative occupational dermal post-application exposure 

assessment for rotenone. Based on the Agency's current practices, a quantitative occupational 

post-application inhalation exposure assessment was not performed for rotenone at this time. If 

new policies or procedures are developed, the Agency may revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for rotenone. 

Conclusions for Occupational Assessment: The occupationaJ exposure database is adequate to 

support the Registration Review process for rotenone; however, there were risk estimates of 

concern identified in 2006 assessments. Since occupational handler exposure estimates were 

based on surrogate data from the Pesticide Handlers Exposure Database (PHED), chemical 

specific rotenone data on the handler exposure scenarios for could provide more refined worker 

risk estimates. 

7.0 Public Health and Pesticide Epidemiology Data 

The Agency has reviewed the available incident data for rotenone (Memo, E. Evans, S. Recore, 

C. Christensen, 0l-APRIL-2015, D427 l 27) and based on the low frequency and severity of cases 

reported for rotenone in both IDS and SENSOR-Pesticides, there does not appear to be a concern 

Page 8of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

at this time that would warrant furthe r investigation for incidents. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment. 

8.0 Tolerance Assessment and International Harmonization 

An exemption from tolerances was originally granted under 40 CFR § 180. l 00 1 (b) for residues 

of rotenone ((2R,6aS, l 2aS)-1.2.6,6a, 12, I 2a-hexahydro-2-isopropenyl-8.9-dimethoxychromeno 

[3,4-b)furo[2,3-h]chromen-6-one) in/on raw agricultural commodities. The exemption from 

tolerances is currently listed under 40 CFR § 180.905. In the last RED, HED recommended the 

tolerance exemption be revoked since all food uses were cancelled. 

9.0 Environmental Justice 

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

most recent rotenone human-health risk assessment, in accordance with U.S. Executive Order 

12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lowlncome Populationsa." The 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., and people who may be exposed when harvesting crops. Should these 

highest exposures indicate potential risks of concern, OPP further refines the risk assessments to 

ensure that the risk estimates are based on the best available information. 

10.0 Cumulative 

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 toxi city finding for 

rotenone and any other substances; and rotenone does not appear to produce a toxic metabolite 

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

assumed that rotenone does not have a common mechanism of toxicity with other substances. 

For information regarding EPA's efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals. see the policy 

statements released by EPA's Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cwn ulating effects from substances found to have a common 

mechanism on EPA 's website at http://vvww.epa.gov/pesticides/cwnulative/. 

11.0 Human Studies 

Past rotenone risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. 

Many such studies, involving exposure to many different pesticides, comprise generi c pesticide 

exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Agricultural 

Handler Exposure Task Force (AHETF) Database, and the Agricultural Reentry Task Force 

(ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide generic 

exposure databases, and has found no clear and convincing evidence that the conduct of any of 

them was either fundamentally unethical or significantly deficient relative to the ethical 

n http://www.cpa.gov/compl iance/cnvironmentaljustice/resources/pol icy/exec_ order_ 12898.pdf 

Page 9of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies. 

12.0 References 

Memoranda Relevant to Re2istration Review. 1 Author Barcode 

P.Y. Barnes 

Elizabeth Evans, Shanna 

1

1 

Recore, and Carol 

Christensen 

Judy Facey 

Brian Fin layson. ct al. 

R. David Jones 

sen Sahafeyan 

D343354 

D427 127 

D307384 

http://www. fisheriessociety .org 

/rotenonc/rot. pdf 

0307383 

D42 1308 

D328478 

Date 

September I 1, 2007 

April I, 20 15 

February 2, 2006 

20 10 

May 5, 2006 

August 7, 2014 

June 28, 2006 

Title 

Rotenone: Revised Acute 

Aggregate Dietary and 

Drinking Water Exposure and 

Risk Assessment for the 

Reregistration Eligibility 

Decision 

Rotenone: Tier I Review of 

Human Incidents 

Rotenonc (07 1003). 

Response to Phase I Error 

Comments from Prentiss, 

Inc. on HED's Preliminary 

Human Health Risk 

Assessment 

Planning and Standard 

Operating Procedures for the 

Use of Rotenone in Fish 

I 

Management Rotenone SOP 

Manual 

American Fisheries Society 

Fish Managemenr Chemicals 

Subcommittee - - - Drinking Water and 

Swimmer Exposure 

Assessment for Rotenone 

from the Piscicide Use 

Rotenonc. Section 18 

Emergency Use for the 

Presidio Lake 

Rotenone: Final HED Chapter 

of the Reregistration os Eligibility Decision Document Smith 

RED). PC Code: 071003 ~~~~~~~~~~~~~~~~~~~-'--'--- ~ 

Attachments: 

Attachment 1: Chemical Identity and Dietary Tables. 

Attachment 2: Rotenone Acute, Subchronic, and Chronic Toxicity Profile. 

Attachment 3: Rotenone of Toxicological Doses and Endpoints for Rotenone. 

Attachment 4: Registered Uses for Rotenone. 

Page 10 of 19 
Attachment 1: Chemical Identity and Dietary Tables. 

Table A.1.1: Test Com ound Nomenclature 

Chemical structure 

CK3 0 

0 

..__ __ ~c-"'CH2 

H ......._CH3 

t--"---------- Em irical formula C23 H12 Ou I · Common name Rotenone . 

I UP AC name (2 R,6aS, 12aS)- I .2,6,6a.12. I 2a-hexahydro-2-isopropenyl-8. 9-

~------------1--im ho y_'- ro o,( A-b] furo[2,3-h )chromen-6-o_n_e. __ _ 

CAS Reois r _ __ _,_83-79-4 ~ Chemical Class Rotenoid 

Table A.1.2: The Ph sicochemical Pro erties of Rotenone 

M as t er R d ecor 

OPPTS Guideline Numbers I dcntification 

830.1550 Product ldentit)' and Com os1t1on 

830. 1600 Description of Materials Used to 

Produce the Product 

I MRIDI 

4 

4 

4 1115-0 I 

41 115-01 

830.1620 Description of Production Process 4 

830.1650 Descri tion of Formulation Process 4 

41 11 5-01 

46528-0 I 

41 115-01 830. 1670 Discussion of Formation of 14 Im urities _[ 

830.1700 Prelimin Analysis 4 '-------- 41386-0 1 

830. 1750 Certified Limits 

830.1800 Enforcement Analytical Method 

4 43953-0 1 

447265-0 1, 

445 108-01 

HPLC/UV 

Status 1 Results or *Deficiency 

A 

A -

A 

A 

A 

A 

A 

830.1900 Submittal of Samples EPA Repository, A 44.2% --- TIFA, Inc. 

t------------- -----1-F_t. _Meade, MD.-1---- Expiration Date: 02/22/_2_0_0_6 _ ___ ---1 

.6 30 r __________ 80- 2 __ -1-A __ -1-T_an ____________ _ 

830.6303 Phxsical State 438180-02 A Powder ~------------1--------,----.....----------------i 

t-8_30. _ _6_30_4_0_ do_r __________ +4_38 I 80-02 - t-A Wet chalk 

Temp(s) = No change was observed: the 

830.6313 Stability to normal a~d elevated 441237_

05 loss was less than 5%. Metals = No 

tempe<a'"<es. metals and metal oons __J -+-- I ~~nge was obmved. the loss was about I 

830 . 6 .) ... 14 O x1 'd anon · /R e d UCllOll · Ch em1ca mil I __L 438 180-02 A Incompatibility 

830.6315 Flammability_ 438 180-02 A 

830.6316 Explodability 438180-02 A 

.... ... . . ... 1s,o.6, 17 Stornge Stabohty - A 

None 

Not Aoolicable 

Not Anolicable 

Container I Stability 

Temp . 

Poly bag I Stable 

j22EC 

-

I Duration I 

I 1.0 yr. I _J 

b The EPA 's Office of Water has established maximum concentration levels (MCL) for trichloroethylene (5 ppb) 

and toluene 2000 ppb). However. recent environmental incidents have shown trichloroethylene levels to exceed the 

MCL after applications of rotenone to bodies of water. Most current CSFs either do not list or do not quantify the 

impurities. Therefore, HED is unable to conduct a qualitative or quantitative assessment of the potential risks posed 

by the impurities that may be present by any route of exposure. 

Page 11of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Table A.1.2: The Ph sicochemical Pro erties of Rotenone 

Master Record 

OPPTS G uid li~n- 1 b_e_r_s _____ -+-l-d-en_t_ifi_•c_a_t_io_n--1-S-ta_t_u_s

1

_ IMRIDI -1-R-e-su_1_ts_o_r_*D_efi-1c-ie_n_c_y ___ ___ ~ 

Poly bag I Loss #5% I 0.5 . I 40EC 

830.6319 Miscibilicy 441308-01 A Not A licable 

830.6320 Corrosion Characteristics 441308-0 I A None ---~---~----; ~--------!------~--~~---------------; 830.632 1 Dielectric Breakdown Voltage __ +-4_4 1308-01 A Not Applicab_le _________ ----< 

, 830. 7000 pH --,..4_4_1_3_08_-_0_1 __ _,__A __ ..,.. ot A~ li ab e _ _ 

(MRJD to be 

830.7050 UVNIS absorption assioned 

830. 7100 Yiscosit)'. 44 1308-0 I 

830.7200 Melting Point/Melting Range 441237-02 

830.7220 Boilino Point/Boilino Point Ranoe 

830.7300 Density/Relative Densicy/Bulk 

Density 

1830.7370 Dissociation Constant 

~.7550 Partition coefficient (n-octanol 

ater) shake flask method 

830. 7560 Partition coefficient (n-octanol 

/water) generator column method 

830.7570 Partition coefficient (n-octanol 

/water) estimation by liquid chromatography 

830.7840 Water Solubility: Column Elution 

Method; Shake Flask Method 

830.7860 Water solubility, generator column 

method 

830.7950 Vapor pressure 

438 180-02 

447181 -01 

44 1237-04 

_ ............ 

............... 

441237-03 

I ~-~~~~-9-0 I 

L 

1 A = Acceptable; U = Unacceptable (See *Deficiency) 

A Absorptivity at 235nm & 292 nm 

A Not A licable 

A 160 -163 °C 

A 

A 

A 

------

... ............... 

A 

I:------

PAI is solid at room tern erature. 

Fluffy 0.2400 g/cm3; 14. 70 lb/cu. ft 

Com acted 0.4500g/cm3; 28.10 lb/cu. ft 

PAI no dissociation constant at pH 2-12. 

(OECD Method No. I 12 

K o1w Log P = 4.16 

See Guideline 830.7550 

See Guideline 830.7550 

Solvent = Water; Temperature = 20 °C; 

Avg. Solubility= 0.142 mg/ml 

See Guideline 830.7840 

Not Applicable 

Table A.1.3: Acute Dietary Exposure and Risk for Rotenone at the 95t1• Percentile 

Surface Water and Fish Only 

. I a PAD EDWC Exposure Popu % aPAD lation Subgroup /k /d ) g (ppb) (mg/kg/day) ·gay 

Fema les 13-49 years of 0.015 200 0.0 1111 7 74 

Table A.1.4: Results of the Drinking Water Only Chronic Dietary Exposure Analysis for Rotenone 

Population Subgroup 

1 

General U.S. 

Population 

All In fants(< I year 

old) 

cRfD 

(mg/kg/da).'.2 

0.0004 

0.0004 

I Exposure of 

Concern (ppb) 

140 

40 

Children 40 1-2 yea" old ~004 

I Ch;ldccn 3-6 yem old __ o_.0_0_0_4_-+----40 

Number of Days that Exceed Exposure of 

Concern 

4 in warm water ---- 53 in cold 4-5° C water 

27 in Lake Dav_i"'"s,'-C_A _ ____ _. 

::al91349~a~ __ o_.0_0_0_4 __ ~ ____ 12_0 ___ ~----------------~ 

Page 12ofl9 
Rotenone Registration Review Human Health Assessment Scoping Document 

Attachment 2: Rotcnone Acute, Subchronic, and Chronic Toxicity Profile. 

Technical Table A.2.J: Test .Required for Nonfood Use Pesticides Required I Satisfied 

870.1100 Acute Oral Toxicity........................................................ yes I yes 

870.1200 Acute Dermal Toxicity................................................... yes yes I 

870. 1300 Acute inhalation Toxicity............................................... yes yes 

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

870.2500 Primary Dermal Irritation............................................... yes yes ---1 

870.2600 Dermal Sensitization...................................................... y_e_s ______ .._,._y__e_s.,...-

870.3100 Oral Subchronic (rat)...................................................... yes Yes1 

870.3150 Oral Subchronic (dog).................................................... no no 

870.3200 21 /28-Day Dermal (rat).................................................. no 

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

870.3465 28-Day Inhalation........................................................... CR 

870.3700a Developmental Toxicity (rat)......................................... yes 

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

870.3800 Reproduction (rat}.......................................................... Y._e_s __ 

870.4 100a ChronicToxicity(rat)..................................................... yes I Yes' 

870.4 1 OOb Chronic Toxicity (dog)................................................... yes no I 

870.4200a Carcinogenicity (rat)....................................................... yes yes 

870.4200b Carcinogenicity (mouse) ................................................ yes yes 

870.4300 Chronic/Carcinogenicity (rat)......................................... yes -t yes 

870.5 ! 00 Mutagen~c~ty-Gene Mulat~on - bacterial : ................ es___ ye-s- - -----1 

870.5.>00 Mutagenictty- Gene Mutation - mammalian ............ :···· I ~es yes 

870.5375 Mutagenicity- Structural Chromosomal Aberrations.... yes yes 

870.5395 Mutagenicity- Mammalian Erythrocyte Micronucleus. I yes 

870.5450 Mutagenicity- Rodent dominant lethal assay no I 870.5500 Mutagenicity- Bacterial DNA Damage or Repair Test no 

~ 870.5550 Mutagenicity- Unscheduled D A Synthesis................. no 

870.61 OOa Acute Delayed Neurotoxicity. (hen)............................... no 

1

870.61 OOb 90-Day Neuroto.xi.city (hen)............................................ no 

870.6200a Acute Neurotox1c1ty Screen mg Bat1ery (rat)..... ............. yes 

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

870.6300 Developmental Neurotoxicity (rat)................................. no 

870.7485 General Metabolism (rat)............................................... yes 

no 

_L 

no 

I 

no 

no 

no2 

I ~o no 870.7600 Dermal P 3 enetration, in vivo (male rat}........................... yes 

------·--- 870. 7800 lmmunotoxicity (rat or mouse) yes 1

Rcquiremcnts for !his study arc fulfilled b)• the chronid oncogcnicity rat feeding study. 1 An inhalation ncurotoxicity (rat) sludy (DCI GDCl-071003-20980 was issued 9n006) 

no - --

I 

I 

_J 

'CFR 158.340 (24): Dermal absorption studies required for compounds having a serious 1oxic cffecl as idcn1ificd by oral or inhala1ion studies, for 

which a signilicam route of human exposure is dcnnal and for which the assumption of I 00 percent absorption does 110 1 produce an adequate 

margin of safety. Registrants should work closely with the Agency in developing an acceptable protocol and performing dennal absorption 

studies 

Page 13of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Table A.2.2: Acute Toxicitv for Rotenone 

OPPTS G uideline I Study Type 

I 810.1100 

99.23% a.i. 

I MIRD 

I 

Results 

LDso = I 02 mg/kg (M) 

LDso = 39.5 mg/kg (F) 

Toxicity 

Cate2orv 

I 81-1 

I Acute oral [rat] ___t --- - - - , _ _ _ - - - - - - - --+---- -! +-

00 145496 

870.1200 

I 81-2 

Acute dermal [rabbit~ 43907501 I LDs0 = >5000mg/kg IV 

+ 97.9%a.i. ~ - -1-- - -il 

L 870.1300 

81-3 

Acute inhalation [rat] I LCso = 0.0212 mg/L combined J + 4388260 I LCso = 0.0235 mg/L (M) 

98% a.i. LC." = 0.0194 mg/L (F) 

870.2400 

81-4 I 

43907503 conjunctiva! irritation, PIS 3.3 at I IV 

'870.2500. 1-- 81-5 

Acute eye irr. itation [rab it) 

1 

M11111nal 111 unwashed eyes 

97.9% a.i. hr., cleared less than 24 hrs. 

te dermal irritation [rabbit] 

43907504 

I PIS 0.08 at I h-o-ur_\_v_h-ic_h _ __._ __ l_V_---1 

_ _ 9_7.9% a.i. ~ ecreased to 0 at 72 ho_u_rs_--+------1 

870.2600 L 81-6 

Skm scns;1;za1;on [gu;nca p;g] 

1 

I 

I 43817903 ot a dermal sensitizer _ 98%a.i. __,__ - - -

Table A.2.3: Subchronic, Chronic, a nd Other Toxicity Profile of Rotenone 

L- G uideline#/ Study Type CMIRl ?fi# (y~a //D Results ass1 1cation oses 1 

I 870.3 100 I 

1 82-la Satisfi ed by MRIO 001 56739, 4 1657 10 1 (83-5) 

A 

Day oral toxicity (rat) 

I 

1 0014 1406 ( 1980) -..--NO_A_E_L_=_0_.4_m_g/k_ g/_d_ay-------------i 

870.3150 LOA EL = 2 mg/kg/day based decreased body weight in mid82-1 b Acceptable/guideline d ti 1 (?Oo" ) d h. h d 1 d ti I (..,Oo" ) 

I ose ema es _ / O an 1g - ose ma es an ema es _, / O 

1

90 D I . . (d ) M&F: 0, 0.4, 2, I 0 d d . . . (d . f 6 mg/kg/day - ay ora tox1c1ty og I an treatment-relate 111 a111t1on. urauon o treatment was 2 

~ weeks) 

1 870.3200 I . ---- ------------1 

1

82-2 I Not Availa ble 

2 1 /28-Day dermal toxicity 

1

870.3250 

82-3 

90-Day dennal toxicity 

I Not Required 

I :~~/ 465 t Required. 21/28-Day study with neurological parameters is required (OCI 

- GDCl-07 1003-20980 was issued 9/2006). 

1

90-Day ;nhalat;on tox;c;1y 

870.3700a 

83-3a 

Developmental 

Toxicity (rat) 

I 

00144294 ( 1982) 

Acceptable/guideline 

F: 0, 0.75, 1.5, 3. 6 

I 

mg/kg/day 

(GD 6- 19) 

I 

Materna l NOAEL = not identified 

LOA EL = 0.75 mg/kg/day, based on clinical signs oftoxiciry 

(salivation, rubbing of face and paws on cage in all groups). 

I 

Developmental NOAEL = 3 mg/kg/day 

LOA EL = 6 mg/kg/day based on decreased fetal body we ight 

I (23%). 

Page 14of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Ta ble A.2.3: Subchronic, Chronic, a nd Other Toxicity P rofile ofRotenone 

G uideline#/ Study Type 

870.3700a 

83-3a 

Developmental 

Toxicity (mouse) 

870.3700b 

83-3b 

Developmenta l Toxicity 

(non-rodent/rabbit) 

870.3800 

83-4 

Reproduction 

(rat} 

1 870.4 IOOa 

83-la 

Chronic toxic ity (rat) 

870.4 IOOb 

83-lb 

Chronic toxicity (dog) 

870.4200 

83-2a 

Carcinogenicity 

(rat) 

870.4200 

I 

83-2a 

Carcinogenicity 

(rat) 

MRID# (year)/ 

Classifica tion /Doses 

00141707 (1981) 

(main) 

001 45049 ( 1981 ) 

(range-finding) 

Acceptable/guideline 

F: 0, 3. 9, 15, 24 

mg/kg/day (GD 6- 17) 

Not Availa ble 

0014 1408 (1983) 

Acceptable/guideline 

FO: M: 0, 0.5, 2.4, 4.8 

mg/kg/d 

FO: F: 0, 0.6, 3.0. 6.2 

mg/kg/day 

Fl (M):O. 0.6. 3. 1. 7 

mg/kg/day 

Fl (F): 0, 0.7, 3.7, 8. 1 

mg/kg/day 

I Results 

- Ma - ternal NOAEL - I) mg/kg/day 

LOA EL = 24 mg/kg/day, based on decreased body weight 

( 10%) and body weight gain ( 4 1 %), from range finding study. 

Developmenta l NOA EL = 15 mg/kg/day 

LOA EL = 24 mg/kg/day, based on increased resorptions (3.8 

vs. 0.5 controls), from range-finding study. Accepta ble when 

main a nd ra nge-finding study considered together. 

Pa rental/Systemic NOAEL (M

---~ /F) = 0.510.6 mg/kg/day 

LOAEL (M/F) = 2.4/3.0 mg/kg/day based on decreased body 

weight ( 10-1 3%) and body weight gain ( 16-25%). 

Reproductive NOA EL (MIF) = 2.4/3.0 mg/kg/day LOA EL 

(M/F) = 4.8/6.2 mg/kg/day based on decreased live pups/liner 

in both generations (9. 7-9.9 vs. 11.4-11.8 controls). 

Offspring NOA EL (M/F) = 0.510.6 mg/kg/day 

LOA EL (M/F) = 2.4/3.0 mg/kg/day based on decreased F, and 

F2 pup body weight (8-18%) and body weight gain (mid 20-

26%; high 40-60%). 

Satisfied by MRID# 00156739, 41657101 (83-5) 

[ Not Available 

401 7980 I b/4627430 I 

(1986) NTP 

Unacccpta ble/gu ideli 

nc 

0, 38. 75 ppm 

M: 0. 1.7. 3.4 

mg/kg/day 

F: 0, 1.8, 3.6 

mg/kg/day 

00143257 (1979) 

Unaccepta ble/nonguideline 

M&F: 0. 1.7. 3.0 

mg/kg/day (i.p .. 42 

days, observed fo r 17 

months) 

M&F: 0, 1.7, 3.0 

NOAEL (M/F) = 3.4/3.8 mg/kg/day 

LOAEL = not identified 

Animals could have tolerated a higher dose. MTD not achieved 

No evidence of ca rcinogenicity 

NOA EL = 3.0 mg/kg/day 

LOAEL = not identifi ed 

Animals could have tolerated a higher dose. MTD not achieved 

No evidence of carcinogenicity 

I 

mg/kg/d 

(gavage. 42 days) _,____ ____ J 

Page 15of19 
Rotenone Registration Review Human Health Assessment Scoping Docume!lt 

Table A.2.3: Subchronic, Chronic, and Other Toxicity Profile of Rotcnone 

I I cu;deH"e#/ Sindy Type 

0 

8.>-2b I Carcinogenicity 

(mouse) 

---

1870.4200 

83-2b 

Carcinogenicity I (hamster) 

l 

MRID I # (year)/ 

Classification /Doses 

Results 

40 17980 1a/46274301 NOAEL = not identified 

(1986) LOAEL (M/F) = l 11 / 124mg/kg/day based on decreased body I NTP weight (low: (M) 6-12%, (F) 12-20%, high: (M) 1217%, (F) 

Acceptable/guideline 

0, 600, 1200 ppm No evidence of carcinogenicity 

1 17-26%. 

MoO, 111 ,242 l_ mg/kg/day F: 0, 124, 

265 mg/kg/day --- ---

00143256 (1979) I Unacceptable/nonguideline 

0. 12)-, 2)0, - :>00 - , 1000 

I 

ppm M&F: 0, 10, 2 1, 

42, 83 mg/kg/day (food 

factor of 0.083) 

I NOA EL = 42 mg/kg/day LOA EL = 83 mg/kg/day based on 

decreased weight gain. No evidence of carcinogenicity 

Excessive mortality due to secondary infection; additional 

0 .. .,,roups administered :>00 - and I 000 ppm for .> " or 4 months were 

mated resulting in no viable offspring at I 000 ppm and 

maternal neglect and cannibalization at 500 ppm 

1 870.43_0_0 ___ ___ , 00 156739 ( 1985) NOA EL = 0.3 75 mg/kg/day 

83-5 4165710 1 (1989 LOAEL = 1.88 mg/kg/day, based on decreased body weight at 

I 

Chronic/Oncogenicity amendment) termination [M:7% (mid) and 15% (high); F: 24% (mid) and 

0 7 - 37 5 7- [M: 10% (mid) and 20% (h igh); F: 31 % (mid) and 55% (high)] 

(rat) I Acceptable/guideline 42% (high)] and cumulative weight gain 

, .), . , :>ppm 

M&F: o. 0.375, 1.88. and food consumption in females (9% and 21 % in mid and 

.., 7, g/kg/d (ti d I high, respectively] I :~~:":n of ay oo . . . . I 0.05) No evidence of carc111ogemc1ty -------1 

Gene Mutation 40170506 o evidence of induced mutant colonies over background for 

1

84-2 870.5100 I ( 1988) NTP I y rester strain at any concentration up co I 0,000 μg/plate with 

(Salmonella ryphimurium) study I and without metabolic activation; strains TA 98, TA 100, 

___ j_Acceptable/guideline TA 1535, TA 1537. 

I Gene Mutation I 40 170502 ( 1978) I No evidence of induced mutant over back.ground for any test 

1

84-2 870.5100 Acceptable/ stTain at any concentration up to I 0,000 μg/disk with and 

(Sal111011el/a 1yphi11111ri11111) guideline I without metabolic activation; strains TA98, TA I 00, TA 1535 . 

. TA1537, TA1538. 

ne Mutation 40170505 ( 1984) Evidence of a concentration-related positive response of 

870.5300 Acceptable/guideline I induced mutant colonies over background at 0.25-8.0 μg/mL 

l 84-2 I without metabolic activation; significant cytotoxicity at 4 and 8 

(mouse lymphoma cells) nL. 

Cytogenetics 14017980 I c ( 1986) I N~.evidence of chromosome aberrations up to 100 μg/mL 

870.5375 Acceptable/guideline l without metabolic activation and 250 μg/mL with activation. 

84-2 I 

(Chinese hamster ovary) ~ 

Cytogenetics I 00093702 ( 1981) I Maximum tolerated dose (MTD) was not achieved in either the 

l 870.5385 Unacceptable/non- rat or mouse assays. No evidence of induced 

84-2 guideline I chromatid/chromosome aberrations in rat bone marrow cells up I (mt ' "d mouse) I to 7.0 mg/kg; no significant increase in frequency of 

micronuclei 1 in erythrocytes from bone marrow of mice up to 80 

mg/kg. 

Page 16of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Table A.2.3: Subchronic, Chronic, and Other Toxicity Profile of Rotenone 

I MRID# (year)/ I Guideline#/ Study Type Classification /Doses Results 

Micronucleus 00093702 ( 1981) Negative at oral doses ofO. 10, or 80 mg/kg 

870.5395 Acceptable/guideline 

84-2 (mouse) 

Mitotic gene conversion 00 144292 (1981) No evidence of induced mutant colonies over background for I 

870.5575 84-2 

(Saccharomyces 

cerevisiae) 

870.6200a 

81 -8 

Acute neurotoxici ry 

screening battery 

870.6200b 

1

82-7 Subchronic 

neurotoxiciry screening 

I bait•')' 

6300 

83-6 

Developmental 

neurotoxiciry 

l 

870.7485 

85-1 

Metabolism and I phannacok;n<tks (mt) 

870.7600 

85-2 

Denna! penetration (rat) 

870.7800 

lmmunotoxiciry 

Special st11dies Subacute 

neurotoxiciry 

(rat) 

Acceptable/guideline any test concentration up to I 0,000 ug/plate with and without 

I 

I metabolic activation. Limit dose 5000 μg/plate. 

Not Available 

__ J 

Requested, DCI 2/9/04 (GDCl-071003-20980) -inhalation (rat) in reserve 

Study required pending results of the subchronic inhalation neurotoxicity study. 

00 145496 ( 1984) I Primary route of excretion is in feces; extensive enterohepatic 

I 

Acceptable/non- circulation; some urinary excretion with females greater than 

guideline males: polar metabolites reported in feces but metabolites not 

0.01. 0.1. 5 mg/kg (oral identified 

and iv) 

Not Available 

Not Available 

4527950 I (Betarbet 

et al.. 2000) 

Acceptable/nonguidel 

ine M: 2.5-2.75 

mg/kg/day by i.v. 

Behavioral. biochemical. and neuropathological effects in 

humans: induction of specific neurodegenerative lesions in 

nigrostriatal dopaminergic neurons 

I in fusion for 1-5 weeks ~~~~~~ ~ 

Page 17of19 
Rotenone Registration Review Human Health Assessment Scoping Document 

Attachment 3: Toxicological Doses and Endpoints for Rotenone 

Table A.3: Summary of Toxicological Points of Departure and Endpoints for Rotenone for Use in Human Risk 

Assessments 

Exposure/ Point of Uncertain Level of Concern for Study a nd Toxicological Effects Scenario Deoa rture tv Factors Risk Assessment 

15 mg&g/dav 

NOAEL = 15 UFA= I Ox NOA EL Developmental Toxicity - mouse 

Acute Dietary mg/kg UFH= lOx I 000 (UF) MRID 00141707 

(Females 13-49) UFo= IOx LOA EL = 24 mg/kg/day, based on 

aRID = 0.015 increased resorptions 

mg/kg/day 

Acute Dietary 

(General An appropriate endpoint attributable to a single dose was not identified in the available studies, Population including the developmental toxicity studies including infants 

and children) 

NOAEL= UFA= I Ox 0.375/kgLda):'. Chronic/Carcinogenicity (rat) Feeding 

0.375 UF11= lOx NOA EL Toxicity MRJD41 657 10 1 

Chronic Dierary mg/kg/day UFo= IOx l 000 (UF) LOA EL = 1.88 mg/kg/day , based on 

decreased body weight and food 

cRID = 0.0004 consumption in both sexes 

mg/kg/day 

UFA= I Ox Reproductive Toxicity Study in Rats 

Incidental Oral NOAEL = MRJD 00 141408 

Short- and 0.5 mg/kg/day UFii= JOx Recreational LOC = LOA EL = 2.4/3.0 mg/kg/day (M/F), 

Intermediate-Tenn UFo= IOx 1000 based on decreased parental (M&F) 

body weight and body weight gain 

Oral NOAEL = 

0.5 UF,,= lOx Reproductive Toxicity Study in Rats 

Dermal mg/kg/day UF11=IOx Recreational/ MRID 00141408 

All Durations UFo= IOx Occupational LOC = LOAEL = 2.4/3.0 mg/kg/day (M/F), 

(Dermal 1000 based on decreased parental (M&F) 

Absorption body weight and body weight gain 

factor = l 0%) 

Oral NOAEL = UFA= I Ox Reproductive Toxicity Study in Rats 

Inhalation 0.5 mg/kg/day UF11= lOx Recrearional/ MRJD 00 14 1408 

Short-and l 00% inhalation UFo= lOx Occupational LOC = LOA EL = 2.4/3.0 mg/kg/day (M/F), 

I ntermed iate-Terrn absorption 1000 based on decreased parental (M&F) 

factor body weight and body weight gain 

Oral NOAEL = Chronic/Carcinogenicity (rat) Feeding 

Inhalation 

0.5 mg/kg/day UFA= I Ox Recreational/ Toxicity MRJD 41657101 

Long-Term I 00% inhalation UFH= IOx Occupational LOC = LOAEL = 1.88 mg/kg/day, based on 

absorption UFo= lOx 1000 decreased body weight and food 

factor consumption in both sexes 

Cancer (oral, 

dermal, Classification: No evidence of carcinogenicity 

inhalation) 

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. RID = reference dose (a = acute: 

c= chronic). u1: = uncertainty factor. UF" = extrapolation from animal to human (interspecies). UF11 = potential variation in 

sensitivity among members of the human population (intraspccies). UFo = uncertainty in the database because of missing studies. 

MOE margin of t:xposure. LOC = level of concern. NIA not applicable. 

Page 18of19 
Rotenonc Registration Review Human Health Assessment Scoping Document 

Attachment 4: Summary of Registered Uses for Rotenone. 

Table A.4: Summary of Directions for Proposed Use for Rotenone 

Company 

3 POST 

ROAD 

FOREIGN 

DOMESTIC 

CHEMICALS 

CORP 

DREXEL 

CHEMICAL 

COMPANY 

TIFA 

INTERNATIO 

NAL LLC 

CENTRAL 

GARDEN & 

PET 

COMPANY 

Product Name and EPA 

Registration Number %ai 

ROTENONE RESIN FOR 

MANUFACTURING USE 44.2 

ONLY EPA Registration % 

Number: 6458-5 

CUBE POWDER Fish I 

Toxicant 7.4 % EPA Registration Number: 

6458-6 

DREXEL 7.4% ROTENONE 

WETTABLE POWDER 

EPA Registration Number: 

7.4 % 

19713-316 - CHEM FISH REGULAR 

EPA Reg1strat1on Number. 5% 

Formulat Max. Use directions and limitations based 

ion Type App. on current labels alone; not including 

Rate reference to guidance manual 

This product may be formulated into end-use products for 

the pisicides uses (aquatic uses) 

Wetta ble 

Powd er 

_ _, 

EC 

0.68 lb 

ail A-ft 

& 0.54 

lb ai/A 

ft 

Restricted Use Pesticide. Do not use 

dead fish for food or feed. Do not use 

water treated to irrigate crops. Do not 

allow swimming in treated water 

until throughly mixed. 

Restricted Use Pesticide. Do not use 

dead fish for food or feed. 

82397-1 {_1439-1 7) _______ _ I 

CHEM SECT BRAND 

ROTENONE RESINS 

EPA Registration Number: 

82397-4 

CUBE POWDER FISH 

TOXICANT 

EPA Registration Number: 

82397-5 ( 1439-260) 

PRENTOX CUBE POWDER 

EPA Registration umber: 

89459-13 655-3 

~-~-----tP RENT OX CUBE RESINS 

EPA Registration Number: 

89459-15 655-69 

PRENTOX PRENFISl-1 

TOXICANT 

EPA Registration Number: 

89459-23 655-422 

44% 

7.4 % 

5.0% 

44.2 

% 

5.0% 

--'------1---

P RENT 0 X ROTENONE 

8.74 

% 

FISH TOXICA T POWDER 

EPA Registration Number: 

89459-32 (655-691 

-~-------+-

BR I IT LE EXTRACT OF 

CUBE ROOT 

EPA Registration Number: 

44.2 

% 

This product may be formulated into end-use products for 

the pisicides uses (aquatic uses). 

Wettable 

powder 

0.68 lb 

ai/A-ft 

& 0.54 

lb ai/A 

ft 

Restricted Use Pesticide. Do not use 

dead fish for food or feed. Do not use 

water treated to irrigate crops. Do not 

allow swimming in treated water 

until through! mixed. 

This product may be formulated into end-use products for 

the pisicides uses (aquatic uses). 

This product may be formulated into end-use products for 

the pisicides uses (aquatic uses). 

EC 

Powder 

0.68 lb 

ail A-ft 

&0.54 

lb ai/A 

I ft 

Restricted Use Pesticide. PPE listed 

for m/l/a includes coveralls over 

baseline dermal. protective eyewear, 

and dust/mist respirator. Waterproof 

wader can be worn in place of I coveralls. 

This product may be formulated into end-use products for 

the pisicides uses (aquatic uses). 

89459-43 (655-808 ----!---!---~~-

PRENTOX CFT LEGUMINE 

FISH TOXICANT 

EPA Registration 

Number:89459-48 (655-899) 

5.0% EC 0.54 lb 

ai/A ft 

Restricted Use Pesticide. In 

strea m/ri vers/lakes/reservo i r/ponds 

no more than 0.5 ppm ai. PPE listed 

for mil/a includes coveralls over 

baseline dermal, protective eyewear. 

and dust/mist respirator. Waterproof 

wader can be worn in place of 

coveralls. Signs must be marked 

until less than I .~m formulation. --4---~~--~--

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