UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 14-MA Y-2015 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Profenofos - Review and generation of Data Evaluation Record 

PC Code: 111401 

Decision No.: 499600 

Petition No.: NA 

Risk Assessment Type: NA 

TXR No.: 0057218 

MRID No.: 46025403, 46025404, 46025405, 

46025406 

FROM: Monique M. Perron, Sc.D. 

DP Barcode: D425381 

Registration No.: NA 

Regulatory Action: NA 

Case No.: NA 

CAS No.: 41198-08-7 

40 CFR: 180.404 

Toxicologist, Risk Assessment Branch I (RABI) 

Health Effects Division (HED) (7509P) 

THROUGH: Thurston 

Acting Branch 

Morton 

Chief, RABI 

~ 

HED (7509P) 

TO: Monique M. Perron, Sc.D. 

Toxicologist/Risk Assessor, RABI 

HED (7509P) 

I. CONCLUSIONS 

The acute and repeated comparative cholinesterase assays for profenofos have been 

reviewed and classified as acceptable/non-guideline. 

II. ACTION REQUESTED 

Review the acute and repeated comparative cholinesterase data submitted for profenofos 

(MRID 46025403-46025406). 

Page I of I 

Page 1 of 8
Profenofos/11140 I Comparative 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: ~ ~ 

Signature: 

Date: 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Unpublished.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 Unpublished.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. 

Page 2 of 8
Profenofos/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. 

Page 3 of 8
Profenofos/11140 I Comparative Cholinesterase 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 21.3 

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 

Adjusted 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 study report. 1 Calculated by registrant to account for initial differences in bodyweight at the beginning 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 (SD) 

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 12.8 

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 233.4 224.0 234.0 242.4 170.8 178.8 157.2 172.8 

Page 4 of 8
Profenofos/11 140 I Comparative Cholinesterase 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 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 

--

--

37% 

44% 

--

15% 

48% 

54% 

7.7 

180.0 

11.2 

181.2 

10.l 

183.0 

10.8 

186.8 

7.8 

Page 5 of 8
Profenofos/1 I 140 I Comparative Cholinesterase 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 control group value (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% 

Page 6 of 8
Profenofos/1 1140 I Comparative Cholinesterase Assay (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: ~ ~ 

Signature: 

Date: ~ ~ 

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 immediately prior to dosing and at the time of termination. Rats were terminated 

approximately 3-4 hours post-dosing (time to peak effect). Following exsanguination, the brains 

were removed and blood samples collected to determine brain, erythrocyte, and plasma 

cholinesterase activity. 

Page 7 of 8
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 LOAEL for erythrocyte cholinesterase inhibition was 5 mg/kg with a NOAEL of 1 

mg/kg. 

The LOAEL for brain cholinesterase inhibition was 25 mg/kg with a NOAEL of 5 mg/kg. 

CLASSIFICATION: This study is classified as acceptable/non-guideline. 

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality 

statements were provided. 

Table 1. Erythrocyte (U/L) and Brain (U/g) Cholinesterase Activity 

Males 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±663 3785±622 2023±198** 1376±359** 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± 199 1370±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 means±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.O 1). 

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 

Page 8 of 8