UNITED STATES ENVIRONMENTAL PROTECTION AGENC Y WASHINGTON , D.C. 20460 O FFI C E O F C HEMI CA L SA FETY AND POLLUT I ON PREVENTION

MEMORANDUM


### Date: September 21 , 2015 SUBJECT: Sa b a dill a A lkal oid s: Human Health Assessment Scoping Document in Support of Reg i stration Revi ew. PC Code: 002201 D ecis ion No. : 506017 P eti tion N o .: NA DP B a r c od e : D427827 R eg is tration No. : NA R eg ul a t ory Action : Registration Review Case No.: 3128 Ris k Assessme n t Ty p e : NA TXRNo.: NA CAS No .: 8051-02 -3 M RID No.: NA 4 0 CFR: 170.240

FRO M:

# o~,**~** Karlyn Middleton , M

. S., Risk Assessor /Toxicologist Zaida F igueroa, DrPH , Industrial Hygienist**~"-'-"'"~"r** 

### M ichae l A. Doherty , Ph

.D. , Chemist

### 'J::.'"'/ Risk Assessme nt Branch II , 0 "J
- 

### Health Effects Division (7509P) TH R OUGH: Chr istina Swartz, Branch Chief

# ~ Risk Assessment Branch II**--~~~~~- ---**  

### Dan a Vogel , Director**~** 

### Jess Rowland , Deputy Director**~-~** 

### Health Effects D ivision (7509P) Office of Pesticide Programs TO: Roy Johnson, Chemical Review Manager Risk Management and Implementation Branch V (RMIB V) Pesticide Re-E valuation Division (7508P)

Attached i s the Health Effects Division 's (HED) human health assessment scoping document for sabadilla alkaloids to s upport regi stration review.

Page 1 of 13Executive Summary The Health Effec t s Division (HED ) has evalu ated the availab le data , exposure informat ion , and the most recent human health risk assessment for sabadilla a lkalo id s (Rereg istration E li gibi li ty Decision (RED), 2004)

. HED performed this evaluation in order to determine the scop e of work necessary to support the tolerance exemption and existing registrations

. T he primary source of information fo r this evaluation was the RED ; Spec ia l Review and Reregistration D ivision (SRRD) , 2004) and the Summary ofToxicology Data from the California Environmental Protection Agency (CALEPA , 2001). Sabadi ll a alkaloids are insecticides used for the contro l of th rip s on citrus , avocados , and mangos. The alkaloids are obtained as an extract from the ground seed s from the sabadilla plant , with the primary insecticidal component being veratrine (CAS No

. 8051-02-3), consisting of a complex mixture, with the two primary alkaloids being c e vad in e (crystalli n e veratrine) and veratrid ine (amorp hous veratr ine) , accord in g to the Merc k Index. Sabadilla a lkalo id s act as sod ium c ha nn el agon i sts in the nervous system of insects , resulting in persistent neuroexcitation. During the evalua ti on of the sabadi ll a a lkaloids for registration review, HED identified s ign ificant data gaps. As a result , the Agency met with the registrant to discuss the missing data. The registrant indi cated to the Age ncy their inte nt to submit a fu ll database for review to support registrati on of the sabad ill a alkaloids. Therefore, the sco ping document provides gu idance to the registrant regarding the data needed to support the Section 3 registration. Hazard ldentificationff oxicology The toxicology database for the sabadill a alkalo id s is not comp lete
. Several toxicology studies are missing per current EPA Part 158 Guidelines (40 CFR Part 158). These studies are needed to support registration as a conventional pes t icide (see appe ndi x A, Table A. l). The available studies fo r the sabad ill a a lkalo id s are limited , and include: acute leth ality , oral rat subchronic , rat developmental , and mutagenicity studies (Appendix A , Table A.2). Curre ntl y , study summari e s (provided by CAL EPA) are availab le for the oral rat subchronic and developmental rat toxicity studies ; however, the full study reports need to be submitted to the Agency for review. D epend in g on the results of the s ubmitted study reports , it may be appropri ate to consider waivers fo r certain studies , provided there are adeq uate j ustificati on s for why the studies are not needed. Toxic effects observed in the availa b le studies fo r the sabadilla alkaloids include decreased body wei ght and food co nsu mp t ion , effects in the li ver and kidney (i n creased liver weights , and e levated AST , ALT and BUN levels) , and clinical signs (piloerection , emac iation , polyuria, dark crust arou nd the nose , and decreased activ i ty) in oral rat s ub c hronic studies. In rat developmental studies , decreased body weight (and body weight ga in ) was also seen , as well as a number of cli nic al signs (ataxia , decreased activity , abnormal gait, gasp in g , l abored breath in g , and increased sali vati on) in maternal animals. D ecreased body weight and misaligned and unossified sternebrae w ere observed in fetuses in the presence of comparable maternal effects. Therefore , no evi d ence of increased susceptib ili ty was seen in the rat developmental studi es . In mice , the only avail able study is a micronucleus assay in w hi ch lethargy and mortality were Page 2 of 13

### noted; however, administration of the test substance was via intraperitoneal injection , which is not relevant for human exposure, and therefore, th e study is of limited utility for the purpose of risk assessment. No other studies are available in mice and, no studies are available in dogs or rabbits. In the last assessment of the sabadilla alkaloids (RED, 2004), endpoints and points of departure ( PODs) were selected for chronic dietary and dermal and inhalation exposure assessments based on the results from a subchron ic oral toxicity study in rats. The no observed adverse effects level (NOAEL) in 

### the study is 250 mg/kg/day (actual dose of 230 mg/kg/day) based on effects (dec reased relative liver weights, e levated serum chemistry (BUN), reduced food consumption and body weights) observed at the lowest observed adverse effect level (LOAEL) of 500 mg/kg/day. However, a NOAEL of 11 

### mg/kg/day was used for risk assessment since an adjustment was made to account for purity ; the NOAEL was estimated by taking 4.83% (total amount of alkaloids in the seed) of the actual dose of230 mg/kg/day (Appendix A, Table A.3). Residue Chemistry/Dietary 

### The res idue chemistry database to support tolerances or exemption from tolerances for residues of the sabadilla alkaloids inion food is needed. Studies addressing the nature of the residue in plants and livestock are needed, as well as analytical methods suitable for enforcement ofthe residue definition in the target crop commodities. Field trials are needed to determine worstcase residues in target crops and a citrus processing study is needed to determine whether or not residues concentrate during processing of citrus into juice , dried pulp , and oil. The residue data need to be supported by adequate analytical method and storage stability studies. Based on the current uses, rotational crop studies are not be needed because the uses are all on pennanent crops . Depending on the outcome of the metabolism studies, field trials, and processing study, a feeding study may be necessary to quantify transfer of residues into meat and milk. The registrant should thoroughly characterize the test substance used in any residue chem i stry studies

. In 

### addition, any residue data generated in support of the registered uses should reflect the currently established use pattern with respect to application rate, pre -h arvest interval (PHI), application methods and timing. The Agency ne eds several studies in OCSPP Guide line Series 860. The registrant is encouraged to consult with the Agency to address questions prior to initiating any residue program. Once the studies are received , the Agency will determine the residues of concern for tolerance-setting and risk assessment purposes , and as needed , will conduct dietary risk assessments to address potential residues in food and drinking water. Residenti a l Exposure 

### There are no registered residential uses or uses resulting in direct residential exposure associated with the sabadilla alkaloids. However, the sabadilla a lkalo id s can be applied v i a ground and aerial equipment and , therefore, there is the potential for indirect exposure related to spray drift.

Page 3of13

### Spray Drift and Volatilization Residential bystander exposures resulting from off-site transport (e.g

. , spray drift or vo l at ili zation) can occur as a result of applications of sabadilla alkaloids. The potential for spray drift will be quantitatively evaluated for each pesticide during th e reg istration rev i ew process and a ll uses for eac h pesticide will be considered concurrently

. The approach is outlined in the revised 2012 Standard Operating Procedures for Residential Risk Assessment- Residential Expos ure Assessment Standard Operating Procedures Addenda l: Consideration of Spray Drift. The Agency has developed a Volatilization Screening Too l and a subsequent Volat ili zation Screening Analysis

. 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 needed for sabadilla alkaloids. 

### Occupational Exposure Sabad ilia a lkaloids are insecticides used for the control of thrips on citrus , avocados, and mangos. The so le end-use product is formulated as a wettable powder that is mixed with water and applied with either aerial or ground equ ipment. Occupational handler and post-application exposures are expected based on the regi stered agricu ltural uses. Based on the use pattern , occupat ional exposure from the registered food uses is expected to be short-term (1-30 days) and intermediate

- term (i.e. , 1-6 months) in duration. Long-term exposures (i.e. , than 6 months) are not anticipated

. Maximum single application rates previously assessed range from 0.03-0.04 lb ailA for agricu ltural crops. Occupational Handler Exposure There is th e potential for dermal and inhalation exposure to occupati onal handlers from the currently registered use pattern of sabadilla alkaloids. HED previously conducted ORE assessments for the**regist~red** agricultural uses (SRRD , 2004). HED based the assessments on exposure data from the Pesticide Handlers Exposure Database (PHED), assumptions for area treated from the Science Advisory Council for Exposure (ExpoSAC) Policy # 9 , and maximum application rates. Handler exposure and risk were calculated at the baseline level of personal protection (i.e. , lon g pants, a long-sleeved shirt , no chemical-resistant gloves , and no respirator) and with the u se of additional personal-protective equipment (PPE) when necessary (e

. g. , chemical-resistant gloves and/or engineering control

- enclosed cockp its

- for aerial applications). Short- and intern1ediat e-term occupational handler MOEs were not of concern (i.e., MOEs**I** 00 ; LOC = lOO) for all re g istered uses . Since the previous review, there hav e been several updates to HED 's exposure policies , including updated exposure data for occupational handler assessments and update s to bodyweight assumpti ons. These assessments will be revised during registration review to reflect current Agency policies, data , and assumptions.

Page 4of13

### Occupational Post-application Exposure The previous risk assessments evaluated a number of representative occupational postapplication scenarios based on the registered uses (SRRD , 2004). Per the updated Part 158 data requirements (2007), one or more dislodgeable foliar residue (DFR) studies are needed when a pesticide has occupational uses that could result in 

### post-application dermal exposure. EPA needs the 40CFR DFR data (OCSPP 875.2000 and 875.2100) to facilitate any necessary exposure assessment refinements due to changes in toxicological endpoints and to further EPA ' s general understanding of the availability of dislodgeable foliar pesticide residues for sabadilla alkaloids. The restricted entry interval (REI) for agricultural occupational exposure is the time period following a pesticide application during which entry into the treated area is restricted

. The REI established for sabadilla alkaloids is 12 hours. Since the RED , there have been several updates to HED ' s exposure policies, including updated exposure data for occupational post

- application assessments. Occupational post-application assessments will be revised during registration review to reflect current Agency policies and to ensure that the REis are adequate to protect workers from post-application exposures to sabadilla alkaloids

. Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for sabadilla alkaloids

. However, if new policies or procedures are put into place , the Agency might revisit the need for a quantitative occupational postapplication inhalation exposure assessment for sabadilla alkaloids during registration review. Data Deficiencies, Label Revisions, and Risk Assessmen t Needs Data Needs 

### Toxicology There are several outstanding toxicity studies for the sabadilla alkaloids , studies which are typically needed for registration as a conventional pesticide. Currently , the available toxicity studies are limited and include: acute lethality data (which were reviewed by EPA) , rat subchronic oral and developmental rat toxicity studies, and mutagenicity studies (all reviewed by CAL EPA). Provided the available CAL EPA studies are adequate (study reports should be provided by the registrant), the studies listed below are required. 

### Ifthe CAL EPA studies are no adequate , additional data may be needed. It 

### is possible that some of the studies could be waived based on the results of other studies (see Appendix A for specific guideline numbers). Once the required studies are submitted , HED will provide updated hazard characterization and endpoint selection for dietary and occupational risk assessments; in addition , as needed , an oral endpoint will be selected for the purpose of the spray drift assessment. Guideline No. Study Description 870.3150 90 Day Subchronic Dog: a one year dog is only required if the chemical is highly bioaccumulating and is eliminated so slowly that it does not achieve Page 5of13steady state or suffic ient tissue concentrations to e li cit an effect during a 90-day study). EPA would requ ire the appropriate tier II metabolism and pharmacokinetic studies to evaluate more precisely bioavailability, ha lf-life , and steady state to determine if a longer duration dog toxicity study is needed.

870.3200 21 or 28 day dermal
21 / 28 or 90 day inhalation: required if there is the likelihood of significant repeated inhalation exposure to the pesticide as a gas, vapor , or aerosol. Based 870

. 3465 on estimates of the magnitude and duration of human exposure , studies of shorter duration, e . g. , 21- or 28-days , may be sufficient to satisfy this requirement. Registrants should consult with the Agency to determine whether stud ies of shorter duration would meet this requirement.) 870.3700b Developmental Rabbit 870.3800 Reproduct ion Rat 870.4200 Carcinogenicity Mouse and Combined Chronic/Carcinogenicity Rat 870.6200 Neurotoxicity Battery: Acute and Subchronic Neurotoxicity 870.7800 Immunotoxicity 870.7465 Metabolism and Pharmacokinetics
Residue Chemistry: The following res idue studies are required to support the registered uses on citrus , avocado and mango; once these data are subm itted , HED wi ll determine the need for to lerances , the residues of concern for risk assessment and tolerance-setting , and will conduct a dietary exposure assessment based on the potential for residues in food and drinking water sources. Note that estimated drinking water concentrations will be determined by the Environmental fate and Effects D ivision (EFED) , depending on the outcome of any required fate studies

.

Guideline No. Study Descripti on 860. I I 00 Chemical identity 860.1650 Submittal of analytical reference standards 860.1300 Nature of the residue in p l ants 860.1300 Nature of the residue in livestock 860.1340 Residue analytical methods 860

. 1360 Mu ltiresidue method 860.1380 Storage stability Page 6of 13

### Guideline No. Study Description 860

. 1500 Crop field trials 860.1520 Processed food or feed 860

. 1480 Meat/milk/poultry /eggs Occupationa l /Residential Exposure: HED will conduct updated occupational handler and post

- application assessments , based on the registered use pattern, and on relevant endpo ints and doses for risk assessment. The required DFR study will be used to determine post-application dermal exposure and risk.

• 875.2000, 2100 Dislodgeable Fo liar Residue (DFR) Dissipation Study. DFR data are required for the registered uses. Risk Assessment Needs/Updates After receipt of the new toxicology data , HED will consider the appropriateness of the existing endpoints based on the new data and current policies and risk assessment methodologies. After review of the submitted residue data, HED wi ll set appropriate tolerances as needed. In addition, di etary risk assessments will be conducted based on the potential for residues in food and drinking water. HED will also conduct revised occupational exposure assessments to reflect the use of the most recent exposure data, new tox ic ity endpoints and PODs, and updated exposure inputs. Endocrine Disruption As required by FIFRA and FFDCA , EPA reviews numerous studies to assess potential 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 studies 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 part of its most recent registration decision for the sabadill a a lkaloids , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), the sabadilla alkaloids are subject to the endocrine screening part 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 " naturally 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 1 1 screening assays to identify the potential of a Page 7of13chemical 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 avai lable data. Tier 2 testing is designed to identify any adverse endocrine -rel ated effects caused by the substance , and estab li sh a dose-response 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 -in s for the first group of 67 chemicals , which contains 58 pesticide acti ve ingredients and 9 inert ingredients. A second list of chemica ls identified for EDSP screening was published on June 14, 2013Pl and includes some pesticides scheduled for registration review and chemicals found in water. Ne ither of these li sts should be construed as a list of known or likely endocrine disruptors

. For further information on the status of the EDSP , the policies and procedures , the lists of chemical s, future li sts, the test guidelines and the Tier 1 screening battery, p lease visit our website

. Public Hea lth and Pesticide Epidemiology Data Both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/N IO SH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were consu lted for pesticide incident data on the active ingredient (ai) sabadilla alkaloids. The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to sabadilla alkalo id s exposure. Sabadilla alkaloids is not included in the AHS , and therefore this study does not provide information. Overall , there are few incidents reported to ID S involving sabadilla alkaloids. For the Main IDS , from January 1 , 20 1 0 to February 4, 2015 , there were no incidents reported involving sabadilla alkaloids

. In Aggregate IDS , from January 1 , 2010 to February 4 , 2015 , there were 3 incidents reported involving sabadilla alkaloids

. These incidents were classified as minor severity. A review of SENSOR-Pesticides 1998-2011 identifies a total of three cases, stemm in g from three events, involving sabadi ll a alkaloids (PC Code 00220 I). Two cases invo lved a single active ingredient. Both single ai cases were low in severity. One case was work-re lated and in volved a nursery worker who "walked by trees that had been sprayed with a hand sprayer and the spray was st iII in the air. " This case reported respiratory (cough , respiratory irritation and shortness of breath) , gastrointest in al (nausea) , neurological (headache and muscle weakness) and cardiovascular (hypertension) symptoms. The second case involved a homeowner making an application to his residence and reported dermal , respiratory (cough) and gastrointestinal (diarrhea) symptoms
.

Il l See http ://www.regulations.gov/# !documentDetail:D= EPA

- HQ-OPPT

-2009

-0477

- 0074 for th e final second list of chemicals. Page 8of13

### Based on the low frequency and severity of incident cases reported for sabadi ll a alkaloids in both IDS and SENSOR-Pesticides , there does not appear to be a concern at this time that wou ld warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered , additional analys is will be included in the risk assessment. 

### E nvironmental Ju s tice Potential areas of environmenta ljustice concerns , to the extent possible , were considered in the human-health risk assessment , in accordance with U.S

. Executive Order 12898 , " Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations ," (http :// www. h ss .e nergy.gov/nuclearsafety/env/ g ui dance/justice/eo 12898

. pdt)

. T h e OPP typically considers the highest potential exposures from the legal use of a pesticide wh en 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 might be exposed when harvesting crops. Should these highest exposures ind icate potential risks of concern , OPP further refines the risk assessments to ensure that the risk estimates are based on the best avai l ab le information

. 

### Cumulative Ri s k Assessments Unlike other pesticides for which EPA has followed a cumulative ri sk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to the sabadilla alkaloids and any other substances , and the sabadill a alkaloids do not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore , EPA has not assumed that the sabadilla alkaloids 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 cumula ting effects from substances found to have a common mechanism on EPA ' s website at 

### http : //www . epa.gov/pesticides/cumulative /

. Human Studies The previous sabadilla alkalo id s risk assessments relied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Studies such as the Pesticide Handlers Exposure Database (PHED) , Outdoor Residential Exposure Task Force (ORETF) , and Agricultural Handler Exposure Task Force (AHETF) have been rev iewed by the Agency and found , on the basis of avai lab le evidence, to have been neither fundamentally unethica l nor significant ly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no barrier in EPA ' s " Protection of Human Subjects " Regulation to relianc e on these studies

.

P age 9 of 13Referenc es: A utho r B arcode Date T itl e S

. Recore 0427879 6/23/2 015 Sabadill a alkaloids: Review of Human Incidents US EPA : NIA 9/27/2004 Reregistration Eligibi li ty Decision: Exposure and Special Review Risk Assessment on Lower Risk Pestic ide and Chemical s. Reregistration Division (SRRD)

Appendix A. Toxicology Data Req uirement s and Tox ic ology Profile The toxicology requirements (40 CFR 158.340) for the sabadilla a l ka loids are prese nted be low. The missin g stud i es are in bold

. Table A.1. Toxicology Data Req u irements

. Test Technical Required Satisfied 870.1100 Acute Oral Toxicity

.. . .................. .. .. .. ... . ... . ....... . ........... yes yes 870.1200 Acute Dermal To xic ity

. ................... .. .. .. ... . .. .. ....... . ....... yes yes 870.1300 Acute Inh a lation Toxicity

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

. . ... . ... . ....... .. . .. ... .. .. . ... . ... . ........ . ... yes yes 870.2500 Primary D ermal Irritation

. ........... . ............... . ... .. ........... yes yes 870.2600 Dermal Sensitization .............. . ....... . .. . .. ....... . ... .. ...... . ... . yes yes 870.3100 Oral Subchronic (rat)

...... . ....... . ............... .. .................... yes yes+ 870.3100 Ora l Subc h ro ni c (mo u se)

........................................... yes no 870.3 1 50 Ora l Subc h ronic (dog)

.. ....... ..................... .. ............... yes no 870.3200 21 /28 -D ay Dermal

...... ... .................. .. ......... .. ............... yes no 870.3250 90-Day Dermal

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

### --- 870.3465 21 /28

- Day Inh a lati on .................................................. no x 

### --- 870.3700a D eve lopmental Toxicity (rat)

...... .... ..... .. .. .. .. . .. .. ... .. ...... yes yes+ 870.3700b Developmental Toxicity (rabb it)

.. ...... .... .. .. ............. .. yes n o 870.3800 Reproduction ( r at)

..................................................... yes no 870.4200 Carc in ogen i city (mo use)

............................................ yes no 870.4300 Comb in ed C h ronic/Carc in ogenic ity (rat)

................ yes no 870.5100 Mutagenic ity

- Gene Mutation - bacterial.

. ... .. ........... . . yes yes + 870.5300 Mutagenicity-Ge ne Mutation

- mammalian

.............. yes yes + 870.5375 Mutage nicity-S tructural Chromosomal Aberrations

. . yes yes* 870.5395 Mutage nicity

- Micronucleus

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

............................. no -- - 870.6100b 90-Day Neurotox ici ty (hen)

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

## --- 870

. 6200a Acute Neurotox ic ity Screening Battery (rat)

. ... ....... yes no 870.6200b 90 Day Neurotox ic ity Screenin g Battery ( r at)

......... yes no 870.6300 Develop. Neurotoxicity

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

## ---

P

age 10 of 13Table A.1. Toxicology Data Requirements. Test Technica l Required Satisfied 870.7485 Genera l Metabo li s m ........................................ .. ......... ye s no 870.7600 Dermal Pe netration

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

## --- 870 .7800 lmmunoto x ic ity ......... . ................................................ yes no *f

ulfill e d by g uid e lin e 870

. 5300

. + The full s tud y re po rt need s to b e s ubmitted to th e age nc y for re view to determin e the accep tabilit y o f th e s tudy (summary a vail a ble). x The inh a lation toxicity s tudy i s ty picall y nee de d i f th e r e is th e likelihood o f s ig ni fi cant re pe a ted inhal a ti o n exp os ure to th e pes ticid e as a g as , vapor, or aeroso l.

Tab le A .2 . Toxicity P rofile - Sabadilla Alkaloids. Acute Toxicitv G uideline Study Type MRIDI Dos es Results Tox Category 870.1100 Acute Oral

- rat 42405901 LD so > 5000 mg/kg JV 870.1200 Acute Dermal

- rabbit 42405901 LD s o > 2000 mg/kg lII 870.1300 Acute Inhalation MRJD not found LC s o > 2.10 mg/L IV 870. 2 400 Primary Eye Irritation- 42405902 some effects on IV rabbit cornea and iris , plus rednes s of conjunctiva at I hour , but nonirritating (clear) at 24 hours and there after 87 0

.2500 Primary Dermal Irritation- 4 2 405902 No irritation IV rabbit 870.2600 Dermal Sensitization- 42405903 Non-Sensitizin g (no NI A Guinea Pi g (Buehl e r ) dermal response in s cre e n ing , induction , or challenge ohases) Other Toxicity Guideline Studv Tvoe MRID/Dos es Res ults 8 7 0.3100 90 day Subchronic Rat MRID: N/ A CAL EPA NOAEL =250 mg/ kg/day s ummarie s LOAEL: 500 mg/kg/day , decreased 0 , 250, 500 , and I000 relative liver weight s, elevated serum mg/kg/day chemistry (BUN) , reduced food [Sabadilla S eed

- consumption and body weights. 0 , Technical grade (Veratran 250 , 500 , and I000 mg/ kg/ day Technical , purity: 4

. 83 % [Sabadi ll a Seed

- Technica l grade Total Alkalo ids) ] (Veratran Technical, purity: 4.83 % Total Alka loids)] 8 7 0.3 7 00 Developme ntal Rat MRJD : NIA CAL EPA Maternal NOAE L: 50 mg/kg/day s ummari es Maternal LOAEL: 250 mg/ k g/day Dose range: 0, 50 , 250 , ( clinical signs) and 500 mg/ kg/ day [Veratran D , Technical , Developmental NOA E L: 250 as s umed 100 % ] mg/kg/day Developmental LOAE L: 500 mg/kg/day (reduced mean fetal w e ights , as we ll as mi s aligned and unossified stemebrae) P

age 11 of13Tab l e A.2. Toxicitv Profile - S a badilla Alka loid s . 

### . Acute Toxicitv G uid eline Stud y T y pe MRID/Doses R es u l ts 

# I T ox Category 870.5100 Bacterial Reverse MRID: 462833 11 Negative Mutation Assay Dose range: up to 5 , 000 μ g/ ml with or without metabo li c activation. 870.5300 In vitro Mammalian Ce ll MRID: 46283309 Mouse lymph oma c e lls p lated with rat Gene Mutation Do se ran ge: up to 1 , 000 li ve r m etabol ic activation were found μg/m l with or without to exhibit mutant frequencies metabolic activ ation. approx imately two

- fold greater than the so lve nt control. No dose-related re s ponse was observe d and significant toxicity (growth # 50 % of the solvent control) was observed at the 4 hi gh est do ses . 870.5395 Mammal ian Erythrocyte MRID: 46283307 Negative M icronucl eus Dose ran ge: 0 , 17.5 , 35 , 70 mg/k!!/day
Table A.3. Summary of Curr ent Tox ico l ogica l Dose s and Endpoints for Sabad ill a A lka loids for Use in Diet ary, Non-Occupationa l and Occupati onal Human Health Risk Assessments. RfD ,PAD , L e ve l of Unce r tainty/ Concern for Expos u re/ Point of F QPA Safety Risk Sce nari o D e parture Factors Assessment Study and Toxico lo g ical E ffects Chronic NOAEL = UF A = IOx Chron ic RID NOAEL= 11 mg/kg/day used for ri sk Dietary (All 11 UF11 = lO x = cPA D = assessment (estim ated by taking 4.83% Populations) mg/kg/day FQPA SF = lx 0.11 (total amount of alkaloids in the seed) of mg/kg/day the actual dose of230 mg/kg/ day) Dermal Short

- NOAEL = UFA = IOx Occupational NOAEL: 250 mg/kg/day Term ( 1-30 11 U FH = I Ox LOC for LOAEL : 500 mg/kg/day , decreased days) mg/kg/day FQPA SF= Ix MOE = 100 relative liver weights , elevated serum chemistry (BUN), reduced food OAF = cons umpti o n and body we ights. 0 , 250 , 100% 500, and I000 mg/kg/day Inha lat io n NOAEL= UF A = IO x Occupational (Sabadilla Seed

- Technical grade (Ye ratran T echnical, purity: 4.83% Tota l Short

- Term 1 1 UF11 = lOx LOC for Alkalo ids)] ( 1-30 days) mg/kg/day FQPA SF = Ix MO E = JOO

Canc e r (o ra l, Carcinogenicity studies are not available. dennal , inhalation) Point of Departure (POD)= A data point or an es timated point that is derived from observed dose-response data and used to mark the beginning of ex trapol ation to determine risk associated with lower e nvironme nt a ll y r e levant human ex posure s. NOAEL = no obs erv ed adverse effect leve l. LOA EL = lowest observed adverse effect le ve l. VF = uncerta inty factor. UFA = extrapo lat ion from anim al to human (interspecies)

. UF11 = potential variation in sensitivity among members of the hum an population ( intraspec ies). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose

. MOE = margin of ex po s ure. LOC = level of concern. Page 12 of 13Page 13 of 13