UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , 

### D.C. 20460

MEM O RANDUM Date: 14-MAY-2015 OFFICE OF CHEMICAL SAFETY AN D POLLUTION PREVENTION

SUBJECT: Profenofos

- Review and generation of Data Evaluation Record

PC Co d e: 111401 Decisio n No. : 499600 Petition No.: NA Risk Assessmen t Type: NA TXR No.: 0057218 MRID No.: 46025403, 46025404, 46025405, 46025406 FRO M: Monique M. Perron, Sc.D. DP B a rcod e : D425381 R egistration No . : NA R egulatory Ac ti on: NA Case No .: NA CAS No. : 41198-08-7 40 CFR : 180.404 Toxicologist, Risk Assessment Branch I (RABI) Health Effects Division (HED) (7509P) THRO UGH: Thurston Morton

# ~ Acting Branch Chief , RABI HED (7509P) TO: Monique M. Perron, Sc.D. Toxicologist/Risk Assessor, RABI HED (7509P) I. C O NCLUSI O NS The acute and repeated comparative cholinesterase assays for profenofos have been reviewed and classified as acceptable/non-guideline. II. ACTI O N RE Q UESTED Review the acute and repeated comparative cholinesterase data submitted for profenofos (MRID 46025403-46025406) .

Page I of IProfenofos/11140 I Comp arative Cholinesterase Assay (rats) (2012) I Page I of5 

### EPA Reviewer: Monique M. Perron, S.D. 

### RABl, Health Effects Division (7509P) EPA Secondary Reviewer: Anwar Y. Dunbar, Ph .D. 

### RABl, Health Effects Division (7509P) Signature:

# ~**~** Date:

# ~~ Signature: 

# qJ 

# = Date: 

### 5" 14- / 

## !.L TXR#: 0057218 ABBREVIATED DATA EVALUATION RECORD 

### STUDY TYPE: Repeat Dose Comparative Cholinesterase Assay PC CODE: 111401 

### DP BARCODE: D4253 81 

### TEST MATERIAL (PURITY) : Profenofos (91.8% w/w) 

### SYNONYMS: CGA-15324 

### CITATION: Milburn, G.M. Profenofos (CGA-15324): Repeat Dose Cholinesterase Inhibition Study in Preweaning and Young Adult Rats. Central Toxicology Laboratory (Cheshire, UK). CTL Study Number KR1504. June 5, 2003. MRID 46025403. Unpublished. Milburn, G.M . Profenofos (CGA-15324): Preliminary repeat dose study in preweaning rats. Central Toxicology Laboratory (Cheshire, UK) . CTL Study Number KR1503. May 23, 2003 . MRID 46025404. Unpublished. 

### SPONSOR: Syngenta Crop Protection, P.O . Box 18300 , Greensboro, NC 27419. 

### EXECUTIVE SUMMARY: In a comparative cholinesterase assay (MRID 46025403) , groups of young adult (5 /sex/dose) and day 12 post-partum pre-weaning (5/sex/dose) Alpk :AP SD rats were given 10 consecutive days of dosing ofprofenofos (98.1% w/w; Lot 667 19888) by gavage at doses ofO, 0.5, 5 , or 50 mg/kg/day in a 1 % w/v aqueous carboxymethyl cellulose vehicle. The dose levels were selected based on the preliminary repeat dose study in pre-weaning rats (MRID 46025404) . Body weights were recorded immediately prior to dosing and detailed clinical observations were recorded at the same time bodyweights were recorded and again at the time of peak effect (3-4 hours post-dosing). Rats were terminated approximately 3-4 hours post-dosing on the last day of dosing. Following exsanguination , the brains were removed and blood samples collected to determine brain , erythrocyte , and plasma cholinesterase activity.Profenofo s/1 1140 I Comparative Cholinesterase Assay (rats) (2012) I Page 2 of 5 One female pup in the low dose group was found dead after 3 doses; however, its death is not considered treatment-related since all other pups were normal throughout the study. There were no treatment-related clinical observations in pups or adults . Bodyweights were decreased in pre-weaning rats (both sexes) at 5 and 50 mg/kg/day (Table 1). There were no treatment-related effects on bodyweight in young adult rats (Table 2). In pre-weaning male rats , erythrocyte cholinesterase activity was decreased from controls by 5% , 44%, and 60% at 0.5, 5, and 50 mg/kg/day (Table 3). In pre-weaning females results were similar with erythrocyte cholinesterase activity decreased from controls by 15%, 49%, and 59% at 0 .5, 5 , and 50 mg/kg/day (Table 3). In young adult male rats, erythrocyte cholinesterase activity was decreased from controls by 37% and 44% at 5 and 50 mg/kg/day (Table 4) . In young adult female rats, erythrocyte cholinesterase activity was decreased from controls by 15%, 48% , and 54% at 0.5, 5 , and 50 mg/kg/day (Table 4). Plasma cholinesterase activity was also inhibited in pre-weaning and young adult rats (data not shown ; see pg. 40 of the study report) . In pre-weaning male rats , brain cholinesterase activity was decreased from controls by 22% , 33%, and 68% at 0.5 , 5, and 50 mg/kg/day (Table 5). In pre-weaning female rats, brain cholinesterase activity was decreased from controls by 9% , 15% , and 59% at 0.5 , 5, and 50 mg/kg/day (Table 5). In young adult male rats, brain cholinesterase activity was decreased from controls by 0.2%, 7% , and 18% at 0.5, 5, and 50 mg/kg/day (Table 6) . In young adult female rats, brain cholinesterase activity was primarily decreased at the highest dose tested (t25%). Overall, there were no age- or sex-dependent differences. The magnitude of decreased cholinesterase activity was larger for erythrocytes than the brain (e.g., in the 5 mg/kg/day dose , erythrocyte cholinesterase activity was decreased 37-49% while brain cholinesterase activity was decreased 7-33%). The LOAEL for erythrocyte cholinesterase inhibition was 0.5 mg/kg bw/day in preweaning and young adult rats. The NOAEL was not established. The LOAEL for brain cholinesterase inhibition was 0.5 mg/kg bw/day in pre-weaning and young adult rats. The NOAEL was not established. CLASSIFICATION: This study is classified as acceptable/non-guideline . COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were provided.Profenofos/11140 I Comparative Cholin esterase Assay (rats) (20 12) I Page 3 of5

Table 1. Bodyweight measurements in pre-weaning pups Males Females Day 12 Mean 24.5 24 .0 22.3 20.7 24.2 23.9 21.8 19.6 Standard 0 .7 1.9 1.8 1.1 2.5 0.7 1.5 0.9 deviation (SD) Day 13 Mean 26.8 26.7 24.2 22.6 26.5 26.4 23.8 2 1.3 SD 0.8 1.9 1.8 1.0 2 . 8 0.6 1.6 1.0 Day 14 Mean 29.3 29.0 26.0 24.3 28.6 28.7 25.4 23.0 SD 0 .9 1.6 1.8 1.1 2.8 0.8 1.5 1.2 Day 15 Mean 31.3 31.6 28.0 25 .9 30 .7 31.3 27 . 1 24 . 6 SD 0.8 1.5 1.8 1.0 2.6 0.7 1.6 1.2 Day 16 Mean 32.9 34.0 29.2 27.8 32.3 33 .3 28.3 26.4 SD 1.0 1.6 1.8 1.1 2 . 6 1.2 1.6 1.2 Day 17 Mean 34.5 36.1 30.6 29.4 33.8 35.1 29.7 28.1 SD 1.1 1.5 1.9 0.8 2.9 1.1 1.5 1.2 Day 18 Mean 37.4 38.8 32.7 31.7 37.3 37.6 31.5 30.1 SD 1.3 1.7 1.8 1.2 3.4 1.3 1.7 1.7 Day 19 Mean 42.6 42 .2 34 . 8 33 . 5 41.4 40.9 33.5 32.0 SD 0.8 2.2 2.3 1.1 4.0 1.0 1.7 1.4 Day20 Mean 47.3 45.9 38.3 36.0 45.8 44.1 36.4 34.7 SD 1.0 2.5 2.5 1.3 4.0 1.0 1.9 1.7 Day 21 Mean 52.3 50 .2 41.7 40 .3 50.4 48 .2 40.4 38.7 (PO%) U22%) (PO%) (t23%) SD 1.4 2.4 2.9 1.9 4.3 0.8 2.1 1.9 Adj usted mean 1 50.2 48 . 7 42.4 43.1 47.5 45.8 41.2 42.8 U16%) (t14%) (t13%) (J10%) Data were taken from pages 34-37 of the stud y report. 1 Calculated by registrant to account for initial diff ere nc es in bodyweight at the beginnin g of the study. Table 2. Bodyweight measurements in young adults Males Females Day42 Mean 182 .6 188.4 197 .0 203 .2 153.4 157.0 148 .0 156.4 Standard 20.5 25.3 14.6 15 .3 13.8 7.8 10.7 11.9 deviation (S D) Day43 Mean 201.2 195.4 202.8 209.8 154.6 162.0 149.4 159.4 SD 20. 8 27.2 13 . 8 14.5 14 .0 8.2 10.3 12 .6 Day44 Mean 206 .2 201.8 211.4 215.2 159 . 8 164.4 153 .0 160 . 8 SD 21.5 27.6 13.1 16 .3 13.7 12.9 13 .0 1 2.8 Day45 Mean 215.8 207.2 218 .2 224.2 159 .2 169.4 156.4 163 . 8 SD 20.3 27.4 14.3 17 .9 9.8 12.5 11.9 13 .0 Day46 Mean 223.6 215.2 224.8 232.4 165.4 172.2 157.4 168 . 6 SD 20.6 27.4 15.5 19.3 12.9 12.7 10 . 6 10.8 Day47 Mean 233.4 224.0 234.0 242.4 170 . 8 178 . 8 157 .2 172.8Pro fe nofo s/11 140 I Comparative C holine sterase Assay (rats) (2012) I Page 4 of 5 SD 21.1 28.3 15.4 18.4 11.8 12.5 11.7 Day48 

### Mean 2444.4 233 .2 244 .2 251.4 178.0 184.6 164 .0 SD 21.8 28.4 16.8 18.0 10.7 16.3 12 . 6 Day49 

### Mean 252.8 237.8 249.2 258.8 174.6 186.6 166.4 SD 23.3 28.4 17.6 17.0 10.8 16.4 13.4 Day 50 

### Mean 260.8 243.4 258.4 266.0 180.4 190.2 169.2 SD 25.9 29.9 18.5 18.7 14.0 16.1 10 .2 Day 51 

### Mean 267.2 252.2 265.0 272.4 186.4 197.4 171.4 SD 24.6 29.3 18.7 18.6 13.7 17.9 12.8 Data were taken from pages 30-33 of the study report.

Table 3. Profenofos Erythrocyte Cholinesterase Activity in Pre-Weaning Rats Dose Level Mean ChE (mg/f<2 bw) ChE U/L± standard deviation Males 0 3364±717 0.5 3203±437

5 1890±290** 50 1357±137** Females 0 3494±380 0 .5 2970±200*

5 1789±206** 50 1422±381** Data were taken from page 39 of the study report n = 5 at all dose levels , except females in the low dose (n=4). * Significantly different from the control group value (p <0.05) . ** Significantly different from the control group value (p <O.O 1 ). Percent Decrease Compared to Control



### -- 5% 44% 60%



### -- 15% 49% 59%

Table 4. Profenofos Erythrocyte Cholinesterase Activity in Young Adult Rats Dose Level Mean ChE (mw'kg bw) ChE U/L ± standard deviation Males 0 2142±232 0.5 2356±255

5 1360±121** 50 1196±60** Females 0 2626±275 0.5 2231±395

5 1374±338** 50 1206±121** Data were taken from page 39 ofthe study report n = 5 at all dose levels, except females in the low dose (n =4). * Significantly different from the control group value (p<0 .05). **Significantly different from the control group value (p <0 .01) . Percent Decrease Compared to Control



### --



## -- 37% 44%



### -- 15% 48% 54% 7.7 180.0 11.2 181.2 10.l 183.0 10.8 186 . 8 7.8Profenofos/1 I 140 I Comparative Cho lin esterase Assay (rats) (2012) I Page 5 of 5

Table 5. Profenofos Brain Cholinesterase Activity in Pre-Weaning Rats Dose Level Mean ChE (mg/kg bw) ChE U/g ± standard deviation Males 0 6.47±2.21 0.5 5.06±1.08

5 4.36±0.24* 50 2 .08±0.35** Females 0 4.93±0.64 0 . 5 4.47±0.25

5 4.17±0.37** 50 2.01±0.13** Data were taken from page 38 of the study report n = 5 at all dose levels , except females in the low dose (n =4) . * Significantly different from the control group value (p <0 .05) . ** Significantly different from the contro l group val ue (p <O .O

I) . Percent Decrease Compared to Control



## -- 22% 33% 68%



## -- 9% 15% 59%

Table 6. Profenofos Brain Cholinesterase Activity in Young Adult Rats Dose Level Mean ChE (m2/k2 bw) ChE U/2 ± standard deviation Males 0 5.11±0.31 0.5 5. I 0±0.44

5 5.47±0.59 50 4.2±0.26** Females 0 5.03±0.56 0.5 4.92±0.28

5 5.12±0.37 50 3.77±0.61 ** Data were taken from page 38 of the study report n = 5 at all dose levels, except females in the low dose (n =4) . * Significantly different from the control group value (p <0 .05). * *Significantly different from the control group value (p <0 .01) . Percent Decrease Compared to Control



## -- 0.2%

7% 18%



### -- 2%



### -- 25%Profenofos/1 1140 I Co mp arative Cho lin esterase A ssay (rats) (2012) I Page I of 2 

### EPA Reviewer: Monique M. Perron, S.D . 

### RABl, Health Effects Division (7509P) EPA Secondary Reviewer: Anwar Y. Dunbar, Ph.D. 

### RABl, Health Effects Division (7509P) Signature:

# ~**~** Date:

## ~ Signature:

### ~ Date: 

### S I 

## /;_sTXR#: 0057218 ABBREVIATED DATA EVALUATION RECORD 

### STUDY TYPE: Acute Comparative Cholinesterase Assay PC CODE: 111401 

### DP BARCODE: D425381 

### TEST MATERIAL (PURITY): Profenofos (91.8% w/w) 

### SYNONYMS: CGA-15324 

### CITATION: Milburn , G.M . Profenofos (CGA-15324): Acute cholinesterase inhibition study in pre-weaning and young adult rats . Central Toxicology Laboratory (Cheshire , UK). CTL Study Number AR7165 . June 4 , 2003 . MRID 46025406. Unpublished. Milburn , G.M. Profenofos (CGA-15324): Preliminary acute cholinesterase inhibition study in 12 day old rats . Central Toxicology Laboratory (Cheshire , UK). CTL Study Number AR7164. May 23 , 2003 . MRID 46025405. Unpublished . 

### SPONSOR: Syngenta Crop Protection , P .O . Box 18300 , Greensboro , NC 27419. 

### EXECUTIVE SUMMARY: In an acute comparative cholinesterase assay (MRID 46025406) , groups of 12 , 22 , and 42 days old Alpk:AP SD rats (5 /sex/dose/age group) were given a single oral dose by gavage of profenofos (98.1 % w/w ; Lot 66719888) by gavage at doses of 0 , 1 , 5 , 25, or 100 mg/kg in a 1 % w/v aqueous carboxymethyl cellulose vehicle . The dose levels were selected based on the preliminary acute dosing study in 12 days old rats (MRID 46025405). Bodyweights were recorded for each animal prior to dosing. On the day of dosing , detailed clinical observations were recorded immediatel y prior to dosing and at the time of termination. Rats were terminated approxi matel y 3 -4 hours po st-do sing (time to peak eff ect) . Following exsanguination , the brain s were remo ved and blood sampl e s collected to determine brain , erythrocyte , and plasma cholinesterase acti vity.Profenofos/111401 Comparative Cholinesterase Assay (rats) (20 12) I Page 2 of2 

### Erythrocyte and brain cholinesterase activity measurements are summarized in Table 1. Data for plasma cholinesterase activity are not shown (see pg. 28 of the study report). There are no ageor sex-dependent differences in erythrocyte cholinesterase activity . For the brain, there were no sex-dependent differences; however inhibition was seen in D12 animals at 25 mg/kg with no inhibition seen in D22 or 042 animals at that dose. The erythrocyte appeared to be the more sensitive compartment with inhibition seen at lower doses than the brain. Additionally, the magnitude of decreased cholinesterase activity for erythrocytes was similar or larger than the brain at the same dose level within an age group (e.g. , in D22 animals of the 100 mg/kg/day dose group , erythrocyte cholinesterase activity was decreased 45% while brain cholinesterase activity was decreased 22-39%) . The L O AEL for eryth rocyte ch olin ester ase inhibitio n was 5 mg/kg with a NO AEL of 1 

### mg/kg. The L O AEL for brain cho lin esterase inhi bition was 25 mg/kg with a NOAEL of 5 mg/kg. CLASSIFICATION: This study is classified as acceptable/non-guideline. C O MPLIANCE : Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were provided.

Table 1. Erythrocyte (U/L) and Brain (U/g) Cho linesterase Activ ity Ma les Females 0 mg/kg 1 mg/kg 5 mg/kg 25 mg/kg 100 mg/kg 0 mg/kg 1 mg/kg 5 mg/kg 25 mg/kg Erythrocyte 012 304 1± 387 2734 ±6 63 3785±622 2023±198** 1376±3 59** 2944±479 2988±376 2382±672 2289±205 (!10%) UJ3%) (!55%) (tl9%) (!22%) 022 2704±437 2457± 559 2609±592 2014±141* 1478± 166** 2438±705 2776 ± 271 2813 ± 120 2056± 218 (!26%) (!45%) (! 16%) 042 2461 ± 164 2202±309 2195±179* 1799± 141** 1101 ± 143** 2433 ± 181 2342±434 2204± 19 9 13 70±223** (!I I %) (! 11 %) (!27%) (!55%) (!9%) (!44%) Brain 012 3.84±0.31 3.95 ±0.44 3 . 80±0 .7 2 .90±0.28** 1 .34±0.49** 4.18±0.55 4 . 11 ±0.5 4. 10±0.48 3 .38±0.46* * (!24%) (!65%) (!19%) 022 6.01 ±0 .95 6 . 11 ± 1.12 6.00±0.63 5 .79±1.05 3.69±0.23** 6.07 ±0.6 6.83±1.63 6.79±0.89 6 . 30±1.15 (!39%) 042 6 .37±0.47 6.74±0.16 6.45±0 .94 7.48± 1.14 7.76±1.68* 5.74±0 .38 7.50± 1.26 8.16±0.78* 8 . 37 ± 1.7* Data were taken from pages 26-27 of the study report. Values are mean s±standard deviations . Values in parentheses are percent decreases from control. n=S except for 012 females in the 25 and JOO mg/kg dose groups (n=4). 

### * Significantly different from the control group value (p <0 .05) . 

### ** Significantly different from the control group value (p <O .O1) . 100 mg/kg 1359±573** (!54%) 1337±262** (!45%) 1295±230** (!47%) 1 .45±0.46** (!65%) 4.74±0.48* (!22%) 5 .72±2 .36