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EPA Reviewer: John Doherty, Ph.D. 

Reregistration Branch II, Health Effects Division (7509P) 

EPA Secondary Reviewer: Linda Taylor, Ph.D. 

Reregistration Branch II, Health Effects Division (7509P) 

TXR # 0050308 

Data Evaluation Record

Study Type: Special Non-Guideline Assessment for RBC Cholinesterase in Humans. 

DP Barcode: D255538 Submission No.: S561108 

PC Code: 059101 Tox Chem. No.: 219AA 

Test Material: DursbanR, 99.8% Chlorpyrifos (Lot No.: MM930503-17) 

Citations: Kisicki, J.C., Seip, C.W. and Combs, M.L., 1999, “A Rising Dose Toxicology 

Study to Determine the No-Observable-Effect-Levels (NOEL) for Erythrocyte 

Acetylcholinesterase (AChE) Inhibition and Cholinergic Signs and Symptoms of 

Chlorpyrifos at Three Dose Levels”, MDC Harris Laboratory, Lincoln Nebraska, 

Study No.: 21438 (for the Harris Project) and DR K-0044793-284 (for DOW 

AgroSciences), April 19, 1999, MRID No.: 44811002. 

Brzak, K.A. "A Rising Dose Toxicology Study to Determine the No-ObservableEffect Levels (NOEL) for Erythrocyte Acetylcholinesterase (AChE) Inhibition 

and Cholinergic Signs and Symptoms of Chlorpyrifos at Three Dose Levels - Part 

B (Pharmacokinetic paraoxonase data)". Toxicology and Environmental 

Research and Consulting, DOW, Study No.: 981176, June 5, 2000. MRID No.: 

45144101. 

Juberg, D.R. and J.L. Mattsson “Updated DOW AgroSciences Response to EPA 

Query Regarding Two Toxicology Reports”. DOW AgroSciences LLC, 

Indianapolis, IN, May 28, 2008, MRID No.: 47436401. Unpublished. 

Sponsor: DOW AgroSciences. 

Executive Summary: In a special acute oral study (1999, MRID 44811002) performed to 

assess effects on human red blood cell (RBC) acetylcholinesterase (AChE), chlorpyrifos (99.8%; 

Lot # MM930503-17) in a gelatin capsule was administered to 6 human subjects/sex/dose group 

at dose levels of 0 (lactose-filled capsule), 0.5 or 1.0 mg/kg (Phase 1). When it was determined 

that there was no inhibition and no adverse reactions in these subjects, a second phase of 6 

human subjects/sex/group were dosed similarly as control and 2.0 mg/kg chlorpyrifos. 

The subjects vital signs (blood pressure, pulse, respiration and temperature were evaluated the 
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morning prior to dosing and at 1, 2, 4, 8, 12, 24, 48 and 168 hours post dosing. In addition 

hematology, clinical chemistry and urinalysis assessments were performed one week post dose. 

Blood was assessed at –10 hours, zero (pre-dose), and at 2, 4, 8, 12, 24, 36, 48, 72, 96, 

144 and 168 hours post dose for RBC AChE activity. Plasma cholinesterase (ChE) was not 

assessed. Blood and urine were collected at selected intervals and analyzed for chlorpyrifos, 

chlorpyrifos oxon, and the principal metabolite 3,5,6-trichloro-2-pyridinol (TCP) to define the 

pharmacokinetics of chlorpyrifos in humans. The paraoxonase (PON1) status was determined for 

each subject. Serum paraoxonase activity was measured against chlorpyrifos oxon, paraoxon, 

and diazoxon, and called chlorpyrifos oxonase (CPOase), paraoxonase, or diazoxonase, 

respectively (MRID# 45144101). Additionally, the PON phenotype (i.e. QQ, OR and RR) was 

determined for each subject. 

Systemic Effects. There were no apparent clinical reactions or changes in clinical 

chemistry parameters related to treatment. 

Pharmacokinetic Data. Chlorpyrifos was detected in the serum of 4 of the 12 subjects 

(2-8 hours post dose) in the1.0 mg/kg dose (range of 1.1-5.6 ng/g) and in 4 of the 12 subjects (2-

12 hours post dose) in the 2.0 mg/kg dose (range 1.3-18 ng/g). TCP was detected in the blood of 

all subjects through 120 hours (0.5 and 1.0 mg/kg) and through 168 hours (2.0 mg/kg). The 

highest concentration of TCP reached ranged from 110-380 ng/g (0.5 mg/kg), 140-610 ng/g (1.0 

mg/kg), and 370-1600 ng/g (2.0 mg/kg). Chlorpyrifos and chlorpyrifos oxon were not found in 

the urine at any dose level, and chlorpyrifos oxon was not found in the blood of any subject. 

Subject #56 (QQ phenotype) the only subject demonstrating RBC AChE inhibition had a peak 

concentration of 18 ng/gm chlorpyrifos at 8 hours following a 2 mg/kg dose, but withdrew from 

the study after 48 hours for a personal problem. This same subject had the highest levels of 

serum (6671 ng/gm) and urinary (22.8 mg) TCP accumulated up to 48 hours. The serum 

chlorpyrifos and serum and urinary TCP data all suggested that this subject absorbed more dose 

than the other subjects on the study. CPOase for this subject was similar to the other subjects 

with the phenotype QQ. 

RBC AChE. Zero time (predosing) baseline RBC AChE ranged from 8143±982 (±12%) 

to 9572±539 (±6%) U/L for males and 8576±556 (±6%) and 9165±709 (±8%) U/L for females 

indicating good precision for the baseline data. These RBC AChE values were within the 

expected range for humans. Only one individual had a decrease in RBC AChE that suggested

inhibition by chlorpyrifos as indicated by being consistently decreased at the critical hours post 

dosing. For this subject (#56, a female dosed with 2 mg/kg), inhibition of RBC ACHE was 

observed at 8 (23% ↓), 12 (maximum 28% ↓), 24 (26%↓), 36 (19%↓) and 48 (21%↓) hours post 

dose. There were no associated cholinergic symptoms reported, although a transient numbness 

in the upper arms in this subject was reported at about 2 hours post dosing or well before AChE 

inhibition and significant levels of TCP in the serum were detected. The proposed LOAEL is 2 

mg/kg/day for RBC AChE based on 28% inhibition in one female subject. The proposed 

NOAEL is 1 mg/kg. 

Classification: This study is classified as RESERVED. This study has a key deficiency, 

namely that no assessments of plasma cholinesterase were made. The study is considered a 

useful assessment for potential RBC AChE inhibition and contains important pharmacokinetic 

data as well as information on the PON status of the volunteers. 
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Compliance:

 No-Data Confidentiality Claims (No claim of confidentiality within the United States), 

GLP and Quality Assurance Statements were provided. The study was said to be conducted in 

accordance with all applicable U.S. guidelines as specified in Title 21 of the Code of Federal 

Regulations parts 50, 556, and 321 and the International Guidelines for Human Testing as 

promulgated in the Declaration of Helsinki (1964 and as amended 1996). 

Part A. Clinical aspects including AChE Assessments (MRID No.: 44811002). 

 Experimental Constants

A. Test Materials:

Test Chemical: 

Chemical: DursbanR - technical name for chlorpyrifos 

Source: DOW AgroSciences LLC 

Lot: MM930503-17 

Purity: 99.8% (scheduled for decertification in June 2003) 

Appearance: White crystalline powder 

CAS # 2921-88-2 

Chemical 

 Name: 0,0-diethyl 0-(3,5,6-trichloro-2-pyridinyl) phosphorothioate 

Negative Control (placebo): 

Chemical: Lactose 

Source: Mallinckrodt N.F. 

Lot: 6279 KXHA 

Purity: Not specifically stated but stated to “meets N.F. requirements” 

CAS # 63-42-3 

B. Human Subjects:

The subjects were recruited from the Lincoln, Nebraska area in response to an 

advertisement. The criteria for selection for inclusion and continuation in the study were 

described on pages 102 to106 of the study report. 

Some of the characteristics of the participants who were actually dosed with either the 

control (lactose) or chlorpyrifos are as follows: 

Number: 30 males and 30 females. 

Occupations: Not stated for each individual. 

Age: Males: 19 to 54 years; Females: 20 to 52 years. 

Weight: Males: 146 to 224 pounds; Females: 98 to 200. 

Race: Males: 28 Caucasian, 1 black and 1 Asian; Females: all Caucasian. 
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Medical Table 4.4 (page 243) presented comments on the medical history of 

 History: each subject. In the opinion of this reviewer, the medical history appeared 

to be typical of a group of 60 humans within this age bracket. There did not 

appear to be any medical conditions that would affect the outcome of the study. 

The only entries for subject #56 were that she was a non-smoker and was 

hospitalized twice for childbirth (12/93 and 10/97). 

Note: Additional tables presented the results of urinary analysis for drugs (cocaine, ethanol and 

cannabinoids) taken from samples at screening and "interim". All entries were indicated as being 

negative. Data were also presented for the results of the pregnancy test and all entries were negative. 

C. Experimental Protocol. The experimental protocol is described in Table 1 below. 

Table 1. Experimental Design. 

 Group Phrase Dose (mg/kg) Subjects Comments 

 A I 

 

 0.5 6 ♂/6 ♀

 B I 

 

 1.0 6 ♂/6 ♀

 D(1) I 

 

 0 

 (placebo) 

 6 ♂/6 ♀

 C II 

 

 2.0 6 ♂/6 ♀

 D(2) II 

 

 0 

 (placebo) 

 6 ♂/6 ♀

Blood sampled at -10 and 0, hr pretreatment 

and at 2, 4, 8, 12, 24, 36, 48, 72, 96, 120 144 

and 168 hours post treatment and analyzed for 

RBC AChE, chlorpyrifos and its metabolites. 

Urine, blood pressure, pulse, ECG and body 

temperature and clinical laboratory 

assessments were made at pretest and one 

week after administration of placebo or 

chlorpyrifos. 

The subjects were released from the study 

after 7 days. 

 Total Subjects = 30 ♂and 30 ♀. 

Phrase I was conducted first and when it was determined that there was no inhibition of RBC AChE and there were 

no adverse effects, Phrase II was initiated. Phase I groups were dosed on 10/3/98 and Phase II groups were dosed on 

10/17/98. 

C. Basis for Dose Level Selection: 

The low dose of 0.5 mg/kg was based on a previous study (Nolan, 1984; MRID

00124144) in which this dose level produced decreases in plasma ChE by 80% but had no effects 

on RBC AChE and did not result in clinical signs. This dose was included to provide a NOEL 

for RBC AChE. The next higher dose of 1 mg/kg was thought to be a dose where noticeable 

RBC AChE might be expected without showing clinical signs in the subjects. The higher dose 

of 2 mg/kg was initiated when it was established that there was no inhibition of RBC AChE at 1 

mg/kg in order to reach a level where noticeable inhibition of RBC AChE might be attained. It 

should be noted here that administration of the chlorpyrifos in this study was in a capsule, 

whereas chlorpyrifos was applied to a lactose tablet in the Nolan study. 
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D. Dosing Data

Each subject was dosed based on his/her body weight and chlorpyrifos was weighed out 

to the 0.1 mg and placed in white opaque number zero capsules the day prior to dosing. The 

capsule was "filled with lactose" and then closed prior to dosing. Data on the actual mg of 

chlorpyrifos administered to each subject that received the chlorpyrifos were presented in Table 

4.27, page 545. This table presents the weight of the capsule, the weight of the capsule plus the 

chlorpyrifos as well as the weight plus lactose and the subject’s weight to assure that each 

subject was administered the proper dose in mg/kg. For example, subject #56 had a body 

weight of 87.7 kg and was dosed with 173 mg of chlorpyrifos (268 mg weight of capsule plus 

chlorpyrifos - 95 mg weight of capsule). The dose this person in the 2 mg/kg dose group 

received was 173 mg/87.7 kg = 1.97 mg/kg. 

The subjects arrived at the clinic the day before scheduled dosing and at 8 PM were given 

a "snack" but fasted for the next 10 hours. The subjects were given a bracelet with a unique bar 

code to identify specimens collected. Starting at approximately 7 AM, each subject was given 

his/her dose of either lactose only or chlorpyrifos containing capsule. Each subject was watched 

to assure the capsule was swallowed. Following swallowing, each subject was given 240 mL of 

water and it was assured by the study team that the capsule was swallowed. The subjects were 

given their lunch at approximately 11:30 AM and dinner at 4:30 PM and then a snack at 8:30 

PM. The subjects were kept at the clinic for 48 hours and were required to return to the clinic at 

72, 96, 120, 144 and 168 hours after initial dosing. Although the subjects were asked about 

strenuous activity prior to coming to the clinic, there were no comments on the level of physical 

activity the subjects were allowed following dose administration. There were restrictions on the 

consumption of alcohol and tobacco as well as non-prescription and prescription drugs. 

In response to several inquiries that HED made regarding why alternates were needed 

and the fate of some of the subjects, the DOW company responded in a supplemental report 

(2008, MRID 47436401). This report indicated that alternates were used because some of the 

originally assigned subjects either were late reporting or reported with various symptoms that the 

staff determined might affect the study. Of the alternates used there remains one subject (#47) 

where there is some confusion as to whether or not his dose was correct based on conflicting 

body weight and dose administered data. It cannot be determined with certainty if this person 

was dosed at a rate of 1.63 mg/kg or his group dose of 2 mg/kg. 

C. Statistics 

(Reproduced from the study report page 23-25). 

Demographic variables: Descriptive statistics (mean, standard deviation. minimum, maximum, 

and sample size) were calculated for continuous demographic variables (age, height, and weight) 

and frequency counts were tabulated for categorical demographic variables (gender, race, and 

frame size) by gender, by treatment group, and by phase. 
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Vital signs: For each phase, descriptive statistics were reported for all vital signs measurements 

(sitting systolic and diastolic blood pressure, pulse, respiration rate, and temperature) at each 

time point of collection. If a vital signs measurement was re-tested prior to dosing, the re-test 

value was used, instead of the original value, to calculate the descriptive statistics. However, if a 

re-test was required for a post-dose assessment, the original value was used to calculate the 

descriptive statistics. All collected data were included in the summarization of vital signs 

assessments. Where individual data points were missing, data were summarized based on 

reduced denominators. 

Signs and symptoms: Signs and symptoms were coded using the 5th Edition of the COSTART 

Adverse Event dictionary. These data were tabulated by the number of subjects reporting at least 

one symptom and as percent of number of subjects dosed in each treatment group. 

RBC AChE: RBC AChE concentrations were presented by subject and blood collection 

timepoint and were summarized by treatment group and gender using means and standard 

deviations. RBC AChE percent of baseline concentration values were presented and summarized 

in the same way. Percent of baseline at time t was calculated as follows: 

Percent of Baseline1 = (AChE* 100)/baseline 

where AChE represents the RBC AChE concentrations at time t and that individual’s baseline is 

the average of the concentrations collected at time -10 and time 0 predose. All collected RBC 

AChE concentrations were included in the summarization by gender and treatment group. Where 

individual data points were missing, data were summarized based on reduced denominators. 

These percent of baseline data were inspected and a depression of 20% or more in any subject’s 

RBC AChE activity, relative to the baseline and in the absence of a concomitant shift in the RBC 

AChE activity for the control group, was considered a significant depression. 

The RBC AChE activity was also normalized for both baseline and for RBC AChE activity for 

the concurrent control (placebo) group for gender at the time interval. Percent of baseline 

normalized to concurrent control at time t was calculated as follows: 

Normalized Percent of Baselinet = (100*AChEt/baseline) — controlt + 100 

where AChE and baseline are defined as above and control is the mean percent of baseline 

response for the control (placebo) group at time t by gender. These data were presented by 

subject and timepoint and were summarized by treatment group and gender for each timepoint 

using means and standard deviations. 

For the statistical analysis, the normalized data were truncated after 96 hours for Phase 1 and 

after 48 hours for Phase 2 so that there would be a value for each subject at each time point. 

Then the truncated normalized data sets from Phase I and Phase 2 were analyzed, separately, 

using univariate repeated measures analysis of variance (ANOVA) methods and mixed effects 

modeling to investigate if there were statistical differences attributed to treatment. 
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A univariate repeated measures ANOVA was performed as a split-plot analysis with the gender 

by treatment combinations, denoted as group, as the whole plot factor and time as the subplot 

factor. In this setting, the time and group by time interactions are valid only if the data satisfied 

the sphericity property, which says measurements at all time points are equally correlated. Since 

this was not expected to be true, statistical tests were adjusted for the violation of the sphericity 

assumption using Greenhouse-Geisser and Huynh-Feldt adjustments. 

Mixed effects models were also used where gender and treatment were considered to be fixed 

factors and time was considered to be a random continuous covariate. 

This approach allowed the modeling of the effect of gender and treatment over time in a 

structured way, providing the opportunity to identify significant higher-order trends associated 

with AChE inhibition. Covariance structures and terms in the mixed effects models were tested 

using likelihood ratio tests comparing nested models. Covariance structures failing to provide 

adequate fit and terms not statistically significant at the 0.10 level of significance were excluded 

from the model. Differences among the treatment by gender combination pairs were tested using 

contrast statements within the final mixed effects model and were considered statistically 

significant at the 0.05 level of significance. 

All summarization and analyses were conducted using SAS. Output from all SAS programs is 

included in Appendix 3, Supporting Statistical Documents. 

 

Specific Methods and Results

1. Comments on the Subjects and Their Participation During the Course of the Study.

There were sixty individuals (30 males and 30 females) enrolled in the study that were 

actually dosed with chlorpyrifos (36 subjects, 18 males and 18 females) or placebo (24 subjects, 

12 males and 12 females). Of the 60 original subjects selected, about 14 were replaced by 

alternates prior to administration of the dose for various reasons. This is not considered to affect 

the outcome. 

Two subjects, one female placebo (#32) and one female dosed with 2 mg/kg (#56) did 

not complete the study. The former did not return for the day 6, 7 or 8 post dosing assessments 

and was discontinued as per the SOP. Since this subject was in the placebo group, the dismissal 

of this subject is less consequential. The female (#56) dosed with 2 mg/kg chlorpyrifos was 

described as having a personal conflict and did not return on days 4, 5, 6, 7 or 8 for post dosing 

events. This subject will be discussed in the later sections of this review in more detail. 

A third subject (#11), a male dosed with 1 mg/kg did not provide a blood sample at 168 

hours since he was out of the area at the time. He returned to the clinic for subsequent follow up 

investigations (physicals) and was not dismissed from the study. This is not considered 

consequential because 168 hours is well past the expected time of effect of chlorpyrifos. 
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One subject (#6), a male in the placebo group, consumed alcohol on post treatment day 6 

(equivalent to one Margarita). This is not considered consequential to the interpretation of the 

study. 

Five subjects (#s 35, 43, 49, 50 and 60; mid-dose female, high-dose male, high-dose 

female, control female, control female, respectively) either failed to provide urine samples for a 

given interval or did not collect their samples properly such as failure to collect or did not collect 

in the proper container. This is not considered consequential to the assessment of AChE but may 

be relevant to the pharmacokinetic studies. 

2. Clinical Signs and Electrocardiogram

The subjects were instructed to inform the physicians and/or nurses of any signs or 

symptoms that they experienced. They were also asked if they felt that they received the test 

material and if they did why. Vital signs included blood pressure, pulse, respiration and body 

temperature and were assessed on the morning prior to dosing and at 1, 2, 4, 8, 12, 24, 48 and 

168 hours post dosing. The observers that examined the subjects classified symptoms as 

possibly and/or probably related to treatment if a symptom was noted within 48 hours of 

treatment. Since the observers did not know if a subject actually received chlorpyrifos, some of 

the subjects receiving the placebo were said to have symptoms possibly or probably related to 

the test material. 

Appendix Table 1 shows the signs that were indicated by the subjects in either the 

placebo or groups dosed with 0.5, 1 or 2 mg/kg of chlorpyrifos. 

Electrocardiograms (ECG) were done on screening and one week after administration of 

the placebo or chlorpyrifos. Table 4.10 (pages 345 to 351) presented the data for these analyses. 

 All result entries were reported as "normal". There were some subjects with "sinus bradycardia" 

noted at week one post dosing that was not present in the screen but these occurred in the 

placebos as often as in the treated subjects. There were no indications of abnormal recordings to 

indicate that chlorpyrifos affected the heart. The one week interval between the time of test 

material administration and ECG assessment is considered by this reviewer too long to be 

meaningful to detect for an acute response to an OP. 

The study author asserted that “There were no differences noted during this study 

attributed to treatment with regard to signs or symptoms, vital signs or clinical laboratory 

results”. HED reviewers concur with this conclusion. There is no indication that a symptom in 

the treated groups was any greater than similar symptoms in the placebo groups. Other signs 

occurred at times that did not coincide with any indication of inhibition of RBC AChE. 

3. Clinical Chemistry, Hematology and Urinalysis.

Clinical chemistry, hematology and urinalysis assessments were made at pretest 

screening and one week after dose administration. The one week interval following dosing and 
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clinical chemistry, hematology and urinalysis is not considered by this reviewer to be the most 

appropriate time. 

Serum chemistry included: ALT, AST, albumin, alkaline phosphatase, calcium, chloride, 

cholesterol, creatinine, GGT, glucose, inorganic phosphorous, LDH, potassium, sodium, total 

bilirubin, total protein, urea nitrogen and uric acid. 

Hematology included: basophils, eosinophils, HCT, Hgb, lymphocytes, monocytes, 

neutrophils, platelet count, RBC and WBC 

Urinalysis included: bacteria, bilirubin, blood, casts, glucose, ketones, leukocyte esterase, 

nitrite, protein, RBC, specific gravity, urobilinogen, WBC and pH. 

Inspection of the data tables (pages 413 to 454) did not indicate that these parameters 

were affected by chlorpyrifos treatment. It should be noted; however, that subject #56, the only 

subject showing inhibition of AChE, withdrew from study after 48 hours and did not provide 

blood or urine samples for clinical chemistry, hematology or urinalysis. 

4. AChE Assessments.

Analytical Methods for AChE assessment. 

 

Blood was withdrawn via venipuncture on an arm vein and there were a total of 14 blood 

specimens collected per subject (if they completed the study). Once drawn, the blood samples 

were centrifuged for 12 minutes at 3000 rpm and the plasma discarded (except for the 

prescreening sampling). The erythrocytes were then washed with saline and centrifuged for an 

additional 12 minutes at 3000 rpm. The saline was discarded and the erythrocytes were washed 

twice by the same procedure. The resulting erythrocytes were stored frozen and shipped on dry 

ice from the clinical facility located in Lincoln, Nebraska to the MDS Clinical Laboratory 

located in Toronto, Ontario Canada. AChE was assessed by the Ellman method using 

acetylthiocholine as the substrate. The analysis was made using a Hitachi 917 automated 

analyzer. Appendix 5 (pages 547 to 573) described in detail the methods for the preparation and 

assay and mean data for assessment of the RBC AChE by the Laboratory. It was noted that the 

standard protocol for this assay called for initially centrifuging the whole blood for 30 minutes 

(see page 552) and not the 12 minutes as indicated for the subject’s samples in this study. This 

difference is noted but it is not considered to impact the interpretation of the data. 

 An overview of the results of the RBC AChE assessments is presented in Table 2. 

Comments on Table 2 are as follows. Additional mean and individual RBC AChE data are in 

Appendix – 11 in tables A-J. 

The mean results for all groups for RBC AChE data are presented in Appendix 1. The 

mean data for RBC AChE in U/L for the untreated male subjects when assessed at 0 hour ranged 
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from 8143 ± 982 (±12%) to 9572 ± 539 (±6%) for the five different groups. For females the 

range was 8576 ± 556 (±6%) to 9165 ± 709 (±8%). The highest mean for both males and 

females was found in Group B scheduled for dosing with 1.0 mg/kg with chlorpyrifos. 

The mean values for males and females are within the expected range for human RBC 

AChE. In general, the analytical aspects of the measurement of RBC AChE are considered 

appropriate. 

Males. No treatment-related effect was observed in RBC AChE activity at any dose 

level. Column three of Table 2 shows that the mean RBC AChE value for one of the two male 

placebo groups was 10.2% less than the predosing mean and this difference was noted at 144 

hours post dosing. The treated males based on mean data had maximum decreases of -10.7%, -

13.7% for the 0.5, 1.0 and 2.0 mg/kg dose groups respectively when compared to the predosing 

values. These maximum depressions of the means were at 96 hours post dose. Since 

chlorpyrifos is an organophosphate, it would be expected that inhibition would start to occur and 

remain from about 2 hours to over 24 hours. Thus, 96 hours is well past the critical hours for 

expected initiation of inhibition. 

Females. No treatment-related effect was observed in RBC AChE activity at the 0.5 and 

1.0 mg/kg dose levels. At 2.0 mg/kg, one (Subject #56) of the six females displayed RBC AChE 

apparent inhibition (19%-28%) during the 8-48 hour time interval post dose. All other females at 

this dose level showed no definite inhibition. Among females, the two control groups 

demonstrated that there was as much as a 9.6% decrease in RBC AChE and maximum difference 

was again at 96 hours. The treated female groups demonstrated group means of 6.8%, 8.7% 

and 10% lower activity readings for all subjects (but only 6.2% lower when one subject that did 

not complete the study is not included) for the 0.5, 1 and 2 mg/kg dose groups, respectively. 

Thus, the decreases in the means for all treated groups are near the maximum decrease that was 

noted in the placebo group but one subject in the high dose appears to show inhibition. 

The data from several individual subjects are discussed below. 
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Table 2. Overview of the results of the RBC AChE assessments. 

 Group 

 Mean 

Predosing 

 (Hour 0) U/L 

 Lowest 

 Posttreatment 

 Mean (U/L) 

 Highest 

 Posttreatment 

 Mean (U/L) 

 Lowest % 

 for an 

 individual 

D: Control 1 

 Males 

 Females 

 8143±982 

 (12%)1 

 8619±861 

 (10%) 

 7316±598 

 -10.2% @ 144 hr2

 7795±759 

 -9.6% @ 96hr 

 8043±705 

 +2% @ 12 hr 

 8817±884 

 +2.3% @ 8 hr 

88.36% @ 144 hr 

 #103

 83.26% @6 hr 

 #34 

A: 0.5 m/kg 

 Males 

 

Females 

 8998±730 

 (8%) 

 8612±1160 

 (13%) 

 8036±738 

 -10.7% @ 96 hr 

 8028±917 

 -6.8% @ 144 

 9189±924 

 +2.1% @ 8 hr 

 

8938±917 

 +3.8% @ 144 h 

82.68% @ 96 hr 

 #9 

88.62% @ 36 hr 

 #19 

B: 1.0 mg/kg 

 Males 

 

Females 

 9572±539 

 (6%) 

 

9165±709 

 (8%) 

 8263±399 

 -13.7% @ 96 hr 

 

8366±499 

 -8.7% @ 168 hr 

 9862±865 

 +2.9% @ 4 hr 

 

9396±517 

 +2.5% @ 4 hr 

75.47% @ 96 hr 

 #11 

88.99% @ 144 hr 

 #33 

D: Control 2 

 Males 

 

Females 

 9171±1112 

 (12%) 

 

8576±556 

 (6%) 

 8999±1020 

 -2% @ 36 hr 

 

8380±422 

 -2.2% @ 4 hr 

 9425±1041 

 +2.8% @ 72 hr 

 

8941±442 

 +4.3% @ 72 hr 

89.71% @ 144 hr 

 #44 

88.40% @ 144 hr 

 #50 

C: 2.0 mg/kg 

 Males 

 

Females 

 8608±896 

 (10%) 

 

8623±855 

 (10%) 

 8584±806 

 (no difference) 

 

7761±1239 

 -10% @ 12 hr. 

 8089±1088 

 -6.2% @ 12 hr4

 9004±840 

 +4.6% @ 72 hr 

 

8604±1064 

 (no difference) 

89.97% @ 36 hr 

 #48 

71.77% @ 12 hr 

 #56

92.82% @ 12 hr 

 #584

Data are from 5.1.1 and 5.1.2 for Groups A, B, and Control 1 and 9.1.1 and 9.1.2 for Group C and 

Control 2. 

1 The number in () is the standard deviation as percent of the mean for the predosing data. 2

 The percent 
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is the difference between the highest or lowest mean vs. the control at the interval given. 3 The individual 

subject number for the person showing the lowest relative reading for AChE and the interval that this 

reading was made. 4

 Since subject 56 did not complete the study, the reading for the second lowest 

subject is also presented for this group or the mean for the remaining 5 subjects is presented. 

Indications of RBC AChE Inhibition Based on Individual Responses. Note: Additional 

data on the phenotype association with RBC AChE are presented in Appendix 11 Tables. A-C. 

. 

Comment. There is an apparent decrease in the activity noted in Phase I for the males 

and/or females in the placebo, 0.5 and 1 mg/kg dose groups since at hour 96 many of these 

(placebos included) suddenly have readings lower than their previous readings for RBC AChE. 

There was no explanation for this provided. See Table 5.1.2 on page 60 of the study report. 

Since hour 96 is well past the time when chlorpyrifos would be expected to start to cause 

inhibition, the impact of this sudden decrease in activity is not such as to seriously impact the 

interpretation of the data. This sudden decrease in activity was not noted for Phase II of the 

study when both placebo and 2 mg/kg chlorpyrifos were tested (see Table 9.1.2 page 79 of the 

study report). 

Males. Refer to Table H in Appendix. Column five of Table 2 shows that for the 

control group males, one individual demonstrated 11.6% (subject # 10) and another 

demonstrated 10.3% (subject # 44) less than his predosing value. Among the treated groups,

there was a maximum of 17.4% (subject #9), 24.5% (subject #11) and 10% (subject # 48) 

apparent decrease in RBC AChE for the 0.5, 1.0 and 2.0 mg/kg dose groups, respectively. Since 

there are subjects in both the 0.5 and 1.0 mg/kg dose groups that have apparent decreases in 

AChE it can be implied that these individuals may be unusually sensitive to inhibition of AChE 

by chlorpyrifos. Thus, the following will discuss in more detail the overall response of these 

individuals throughout the study. Selected other subjects will also be discussed for the reasons 

given below. 

Subject # 9. Group A. (0.5 mg/kg chlorpyrifos treatment). Subject # 9 was a 19 year 

old Caucasian male 75 inches tall and weighing 210 pounds and was a non-smoker. No clinical 

signs or abnormalities were noted in this person’s clinical chemistry or ECG assessments. This 

subject was reported as having intestinal cramps starting at 2 days, 22 hours and 44 minutes post 

dosing that lasted 15 hours. This subject replied “no” when asked if he had received the test 

material and not the placebo. 

This subject had RBC AChE readings (in U/L) of 8294, 8602, 8437, 8646, 8844, 8723, 

8580, 8261, 8107, 8250, 6985 (-19%), 7535 (-12%), 7376 (-14% ) and 7700 (-11%) for the -

10, zero, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hour assessment times respectively. 

The apparent decrease in RBC AChE did not begin until 96 hours after dosing. It is noted that 

the cramps did not coincide with the lower AChE levels. It was noted above that there is a 

problem with the assays after hour 96 (see comment above). 

At the onset of this subject’s intestinal cramps (~72 hours), his RBC AChE was at most 
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3% less than the zero time reading. However, at 96 hours, his RBC AChE was lowest but his 

cramps had already disappeared by 85-86 hours (see Appendix I). 

In conclusion, there is no justification to support that this individual was unusually 

sensitive to inhibition of RBC AChE. Inhibition would be expected to appear within a few 

hours (~ 4-8 hours) post dosing and not 96 hours later. There were also no symptomatic 

expressions indicative of AChE inhibition (i.e. intestinal cramps are not a specific response to a 

AChE inhibitor and could be due to many things). 

Subject #11. Refer to Table F in Appendix. Group B (1.0 mg/kg chlorpyrifos treatment). 

 Subject # 11 was a 45 year old black male 71 inches tall and weighing 191 pounds and smoked 

one and a half packages of cigarettes a day. This subject did not report for his day 7 

examinations or blood sampling. He did not submit urine for the 144 to 156 hour or 156 to 168 

hour collection intervals. He returned to the clinic “the following week” for a post physical 

exam, ECG and laboratory work up. There was no record of how he responded to whether or not 

he thought he had received the test material rather than the placebo. This subject's clinical 

laboratory work up for post treatment indicated he was “moderately lipemic”. 

On two occasions (refer to page 468 and Appendix 4.21/1) this subject was reported to have a 

headache. The first occasion began 3 hours and 40 minutes post dosing and lasted for 19 hours. 

This means the headache started at 11 am on October 3 and lasted until 6 am on October 4. The 

second occasion began 22 hours and 40 minutes (approximately 6 am on October 4 post dosing 

and lasted 1 day and 9 hours. [There seems to be a reporting glitch here because the first 

headache is reported to be resolved at 6:00 and the second headache starts at 6:00 both on 

October 4, 1998. There may actually be just one headache.] 

This subject had RBC AChE readings (in U/L) of 10307, 10098, 9097 (–10%), 10318, 9768 (-

3%), 9779 (-3%), 9977, 9768, 9141 (-10%), 10153, 7700 (-24%), 9185 (–9%), 9218 (–9%) for 

the -10, zero, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hour assessment times, respectively (not 

assessed at 168 hours). Thus, there was considerable variation in this individual’s readings for 

RBC AChE but they do not fit an expected pattern of inhibition by an organophosphate. Since 

maximum apparent decrease occurred at 96 hours post dosing (again there is a problem with the 

hour 96 readings) and the reading at 72 hours was 10153 or essentially the same as the predosing 

zero hour, this subject is not considered to have chlorpyrifos related inhibition of ChE. 

 

It is noted that there was no consistent depression of RBC AChE during this interval 

when the subject experienced his headache. For example, the readings were -10%, similar, -3%, 

-3%. -3%, and -3% at 2, 4, 8, 12, 24 and 36 hours respectively. 

In conclusion, there is no justification to support that this individual was unusually 

sensitive to RBC AChE inhibition by chlorpyrifos. The headache that this individual was 

reported as having did not coincide with decreased levels of RBC AChE and it was not present 

when AChE was lowest. 
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Subject #47. Group C (2 mg/kg chlorpyrifos treatment, but this subject may have 

actually received a dose of 1.66 mg/kg). Subject #47 was a 24 year old Caucasian male 69 

inches tall and 184 pounds. He responded "no" to the question about whether or not he thought 

he received the test material and did not have any obvious symptoms of AChE intoxication. This 

subject had highest "estimated dose received" (1.130 mg/kg compared with the group mean of 

0.59 mg/kg, see Table 16, page 47 of the Pharmacokinetics report) based primarily on plasma 

and urinary content of TCP. This subject did not have indications of AChE inhibition since 

there was at best a 5% decrease in activity at 24 hours but the preceding and succeeding 

assessments were both higher than the baseline. 

Subject #48. Refer to Table D in Appendix. Group C (2.0 mg/kg chlorpyrifos 

treatment). Subject # 48 was a 23 year old Caucasian male 71 inches tall and weighing 162 

pounds and smoked 10-14 cigarettes a day. He responded no to the question about whether or 

not he thought he received the test material. According to the data table on page 471, this subject 

did not experience any symptoms during the post dosing phrase. 

This subject had RBC AChE readings of 8569, 8206, 8019, 8008, 7887, 7689, 8206, 

7546 (-8%), 7832, 8074, 7766, 7766, 7942 and 8184 for the -10, zero, 2, 4, 8, 12, 24, 36, 48, 72, 

96, 144 and 168 assessment times respectively. Thus, this subject’s maximum decrease at 36 

hours was immediately proceeded by a value actually the same as the zero time assessment and 

thus does not show a pattern consistent with inhibition by an organophosphate. 

Females. Refer to Tables I and J in Appendix. Column five of Table 2 shows that for 

the control group females, one individual demonstrated 16.7% (subject # 34) and another 11.6% 

(subject # 50) less than her predosing value. Among the treated groups there was a maximum of 

11.4% (subject #19), 11% (subject #33) and 28.2% (subject # 56) apparent decrease in RBC 

AChE for the 0.5, 1.0 and 2.0 mg/kg dose groups, respectively. Since the subjects in both the 0.5 

and 1.0 mg/kg dose groups did not exceed the placebo group for apparent decreases in AChE, it 

is not implied that there are individuals in these dose groups that may be unusually sensitive to 

inhibition of AChE by chlorpyrifos. Subjects # 51 and 56 are discussed as follows. 

Subject #51. Phase II Group C female, 2 mg/kg chlorpyrifos. Refer to Table 4 below 

for AChE data on this subject. This subject sustained a decrease of 5 to 6% RBC AChE over the 

critical hours of 12, 24, and 36. However, her pretest variation was also near 5%. This subject 

also had one of the highest levels of TCP in her blood. But the peak level of TCP did not 

correspond with the lower readings for AChE. 

The placebo female group for Phase II was demonstrated to be very stable over the 

course of the seven days on the study (see last column in Table 4) as indicated by the data from 

one individual who demonstrated the most variation of the six females in the placebo group. 

Overall, the 5-6% lower reading in subject #51 is noted but not considered to be definite 

inhibition caused by chlorpyrifos. 

Subject # 56. Group C, 2 mg/kg chlorpyrifos. As indicated previously, subject # 56 
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dropped out of the study after 48 hours. It was originally reported that “repeated attempts were 

made to contact this individual were unsuccessful and no post study medical evaluation was 

performed” (refer to page 28 of the study report). However, the supplementary report (2008, 

MRID 47436401) in response to HED’s questions about the fate of this individual asserts “In, 

1999, Richard Nolan PhD was a DAS toxicologist that was the toxicology contact for the Kisicki 

study. Dr. Joel Mattsson was in 1999 a DAS toxicologist working with Dr. Nolan and was 

assured that the testing laboratory had contacted subject #56 personally and she reported no 

problems with the study but had personal reasons for not returning for further evaluations. DAS 

is not aware of any additional information on subject #56”. There is still ambiguity with regard 

to statements about this subject regarding the comments in the study report (page 28) where no 

contact was made and in the supplementary report (page 17) where contact was said to have been 

made. Overall, failure of this person to have data after 48 hours does not preclude that data on 

AChE assessment and pharmacokinetics obtained prior to 48 hours are not useful and 

informative although the lack of data following 48 hours limits the assessment of the total PK 

picture. The possibility that this subject developed clinical signs in response to treatment cannot 

be resolved on the basis of available information. 

 Page 472 of the study report indicates that this subject reported experiencing 

"numbness of the upper arms" starting 2 hours and 24 minutes after administration of the 

chlorpyrifos and lasting a total of 42 minutes. On page 510, the table listing the subject's 

response to the question if they thought they received the test material does not include subject 

#56. 

This subject was the only subject on the study that demonstrated apparent RBC AChE 

inhibition. Table 3 below provides details about this subject and shows the extent of inhibition 

at the critical time interval. It is apparent that this individual's RBC AChE is decreased starting 

at 8 hours and remaining so until 48 hours when she was last tested. 

Table 3. Summary of Subject #56 

 Parameter Results Comments 

Description (a) A 34 year old Caucasian female 72 inches tall 

and weighing 193 pounds and was a nonsmoker. This individual did not report for the 

day 4, 5, 6, 7 or 8 blood collection (see page 

28) or assessment of vital signs and did not 

provide urine samples after 48 hours. 

There is nothing obviously 

different about this subject to 

suggest an unusual 

susceptibility to chlorpyrifos. 

The subject was genotype QQ 

but about half the persons on the 

study had this genotype. 

Symptoms (b) Subject had a transient "numbness in upper 

arms" that started to occur 42 minutes after 

dosing and lasted for 2 hours and 24 min (self 

resolved without medication). 

The numbness alone does not 

seem to be a response to an 

AChE inhibitor and since this 

occurred and was resolved by 

three hours, or before there was 
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 Parameter Results Comments 

appreciable apparent inhibition 

of AChE at 8 hours post dosing, 

the finding is not considered 

treatment-related. 

RBC AChE 

IU/L 

(c) 

8426 at -10 hours 

8910 at 0 hour 

8668 predosing mean 

8602 (no difference) at 2 hours, 

8525 (-2%) at 4 hours, 

6688 (-23%) at 8 hours, 

6221 (-28%) at 12 hours 

6424 (-26%) at 24 hours 

7051 (-19%) at 36hours

6882 (-21%) at 48 hours 

No additional assessments. 

Subject shows decrease in RBC 

AChE that can be considered 

the critical times expected for an 

OP following an oral 

administration. 

No other subject shows a similar 

pattern of decrease in activity. 

Serum 

chlorpyrifos 

(d) 

18 ng/gm at 8 hours 

 2.5 ng/gm at 12 hours 

All other times - not detected (< 1 ng/gm) 

The highest level in all other subjects was only 

5.6 in a female (#21) dosed with 1 mg/kg. 

Serum TCP 

(0 to 48 hours) 

(e) 

Subject has total of 6671 ng/gm TCP in serum 

with values of 71, 120, 1600, 1500, 1300, 1100 

and 980 ng/gm for the 2, 4, 8, 12, 24, 36 and 

48 hour intervals, respectively. Note there 

was little TCP in blood at 2 to 4 hours or at the 

time the numbness was noted. 

This is the highest (total ng/gm) for the 

group dosed with 2 mg/kg since the range 

for all others (both sexes) was 1404 (#42) 

to 5860 (#47) ng/gm for up to 48 hours. 

Among females, the other five had values of 

2910, 5010, 2730, 2560 and 3310 ng/gm. 

 Urine TCP 

(corrected for 

creatinine) 

(0 to 48 hours) 

According to Table 14b for the 0-48 hour 

interval, Subject 56 had a total of 22.8 mg or 

was highest for the group dosed with 2 mg/kg. 

The range for the others in this group was 4.8 

(#40) to 16.2 (#47) with a mean of 8.4 ± 3 for 

all individuals excluding #56. 

The serum chlorpyrifos data and 

the serum and urine TCP data 

all indicate that subject # 56 

absorbed chlorpyrifos to a 

greater extent than the other 

subjects in this study. 

Since no assessments were 

made after 48 hours, the total 

TCP picture cannot be 

determined to compare with the 

other subjects who seemed to 

have TCP present in the blood 

at the later times. 

Estimated 

internal dose of 

0.640 mg/kg. - from Table 16 

The group mean of 0.59 ± 0.21 mg/kg (range 

The calculation of the total 

internal dose for subject #56 is 

limited since no assessments for 
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 Parameter Results Comments 

chlorpyrifos 

(g) 

0.323 (#40) to 1.130 (#47) mg/kg for the group 

dosed with 2 mg/kg. males 0.61±0.28; 

females: 0.568±0.12 mg/kg based on collection 

for 7 days. 

TCP or parent chlorpyrifos were 

made after 48 hours. 

CPOase (h) Subject has reading of 9278 Units/liter 

comparing favorably with the group mean of 

9523±1517 Units/liter. 

Paraoxonase 367 U/L compared to group mean 

737±430 U/L 

There is nothing unusual about 

the serum activity of CPOase, or 

diazoxonase. Although her 

paraoxonase level was much 

lower than the group mean this 

should not affect dosing with 

chlorpyrifos. Subject was 

described as phenotype "QQ 

low" which was a typical 

classification for many (about 

half) of the subjects in the study. 

 

(a) Data are from Appendix 4.3, page 242.. (b) Data are from Appendix 4.21.1, page 472. (c) Data are 

from Table 4.13.2, page 407. (d) Data are from Table 5, page 34 of the Pharmacokinetics report. (e) 

Data are from Table 7, page 36 of the Pharmacokinetics report. (f) Data are from Table 14b (corrected 

for creatinine), page 45 of the Pharmacokinetics report. (g) Data are from Table 16, page 47 of the 

study report. (h) Data are from Table 17, page 50 of the Pharmacokinetics report. 

It is noted that in the screening study this individual had a RBC AChE of 7678 U/L. This 

was listed as a clinical laboratory comment as “not significant in the context of this study”. 

When compared to the mean for the -10 and zero hour samplings (mean = 8668 U/L), this would 

be 11% less. This value of 11% less is not as much as the approximately 28% decrease that was 

noted for this person following treatment with 2 mg/kg chlorpyrifos. Thus, the decrease in 

AChE after 8 hours is greater than the spontaneous variation for this subject. 

This subject has inhibition rather than random decrease in activity since the decrease in 

activity starts at 8 hours and rises to a peak at 12 hours and then appears to start to decline at 24, 

36 and 48 hours. This would be expected for an organophosphate AChE inhibitor. The pattern 

of decreased activity also correlates with the amount of TCP in the serum as shown in Table 4. 
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Table 4. Correlation between RBC AChE activity and blood level of TCP in humans dosed 

with 2 mg/kg chlorpyrifos. 

Hour 

 Sub. #56(QQ♀)_

RBC TCP 

AChE Blood 

 Sub. #47 (QQ♂)_

RBC TCP 

AChE Blood 

 Sub. #51(OR♀)_

RBC TCP 

AChE Blood 

 Sub. #48(OR♂) 

RBC TCP 

AChE Blood 

Placebo 

#44 (OR♂) 

RBC AChE 

Placebo 

#60 (QQ♀) 

RBC AChE 

 2 = 71 +2% 580 -2% 420 -4% 180 -1% -3% 

 4 -2% 120 +2% 640 -1% 580 -5% 250 = -5% 

 8 -23% 1600 = 790 -2% 1300 -6% 240 -3% +1% 

 12 -28% 1500 = 910 -6% 690 -8% 260 -6% +2% 

 24 -26% 1300 -5% 980 -5% 540 -2% 380 -6% -1% 

 36 -19% 1100 = 960 -5% 750 -10% 460 -4% = 

 48 -21% 980 -1% 1000 -3% 730 -7% 470 -5% = 

 72 +4% 690 +1% 600 -4% 300 +1% -3% 

 96 +2% 460 +4% 420 -7% 210 -4% -3% 

 120 +7% 320 +6% 150 -7% 140 -4% = 

 144 +2% 220 -2% 170 -6% 77 -10% -3% 

 168 

Subject did not 

return for 

additional 

sampling. 

 +7% 150 = 110 -2% 48 = +1% 

Net 

TCP

0 to 48 hrs 6671 

0 to 168 hrs - no 

data 

0 to 48 hrs 5860 

0 to 168 hrs 7700 

 

0 to 48 hrs 5010 

0 to 168 hr s 6410 

0 to 48 hrs 2240 

0 to 168 hrs 3015 

 N/A N/A 

Definitely shows 

inhibition 

correlating with 

blood level of 

TCP. 

Highest levels of 

TCP do not 

correlate with 

↓RBC AChE. 

Sustains a slight 

decrease at critical 

times and is thus 

possibly showing 

inhibition. 

Subject has lowest 

level of blood TCP 

but seems to 

sustain a decrease 

in RBC AChE 

Shows that 

activity 

varies to -

10%. 

Shows that 

female RBC 

AChE is 

stable. 

TCP data are from Table 7 page 36 in MRID No.: 45144101 and are ng/gm. Note: TCP data were not reported for the 

blood from the placebo group in Table 7 of the study report. RBC AChE data are from Table 9.1.2 page 78 from MRID 

No.: 44811002 and are the percent decrease (-) or increase (+) in RBC AChE relative to the baseline. The = sign indicates 
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that the assessment was within ±1% of the baseline. 

 

Table 4 also presents data on the variation of RBC AChE activity in one other female and 

two males dosed with 2 mg/kg of chlorpyrifos and the amount of TCP in their blood. In 

addition, a male and a female from Phase II placebo group are included to show the spontaneous 

variation of RBC AChE. It is noted that the female (#60) is stable but the male (#44) showed 

decreases. One other placebo male (Subject #41, data not shown here because if space 

limitations) also showed what appeared to be sustained decreased activity (4%-7% from 8 hours 

to 36 hours post dose). 

Table 4 indicates that female subject #51 sustains a slight decrease in RBC AChE and 

also has a high blood level of TCP but not at the critical times of lower AChE readings. 

Therefore this subject is not considered to show definite evidence of RBC AChE inhibition in 

response to 2 mg/kg of chlorpyrifos since the level of decrease is too low and not coincident with 

serum TCP. 

 

Part B. Pharmacokinetic and Paraoxonase Data (Refer to MRID No.: 

45144101). 

Part B 1. Pharmacokinetic data. 

Note: Additional data including individual subject data on the pharmacokinetics are in 

Appendix II Tables A-K.. 

The sixty subjects on this study gave blood samples (5 mL) for the purpose of 

determination of chlorpyrifos, chlorpyrifos oxon and 3,5,6-trichloro-2-pyridinyl (TCP) at -10 

hours prior to dosing, at zero hour prior to dosing and at 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 

and 168 hours post dosing. Urine samples from all urine voided (as per the protocol) for the 

intervals -48 to -36 hours, -36 to -24 hours, -24 to -12 hours, -12 to 0 hours pretreatment and 0 to 

6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 to 60 hours, 60 to 72 

hours, 72 to 84 hours, 84 to 96 hours, 96 to 108 hours, 108 to 120 hours, 120 to 132 hours, 132 

to 144 hours, 144 to 156 hours and 156 to 168 hours post treatment. The blood and urine were 

analyzed by GC/MS for chlorpyrifos, its oxon analog and TCP and the method of preparation 

using internal standards was described. TCP was derivitized prior to analysis. 

Data were presented that demonstrated the recovery of spiked samples for chlorpyrifos 

(98.0 to 99.8%), chlorpyrifos oxon (95.4 to 98.0%) and TCP (91.1 to 97.1%), and the lower 

limit of detection was about 1 ng/gm of blood for chlorpyrifos and its oxon analog but was about 

12.1. ng/gm for TCP. Similarly, recoveries of 96 to 104% for these chemicals from urine were 

demonstrated. Additional data demonstrated the stability of these chemicals in blood and urine 

stored -20 or -80 °C for 6 or 10 days. 

Blood and urine analysis for chlorpyrifos and chlorpyrifos oxon.
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Chlorpyrifos and chlorpyrifos oxon were not found in any of the urine samples from any 

of the subjects (refer to Table 10 of the study report page 39). Chlorpyrifos oxon was not found 

in the blood of any subject (refer to Table 6 of the study report page 35). 

Chlorpyrifos was found only occasionally in the blood (refer to Table 5 page 34 of the 

study report). No subjects dosed with 0.5 mg/kg chlorpyrifos were found to have chlorpyrifos 

in their blood. Subjects #11 (1.0 ng/gm at 2 hours), #14 (2.7 and 1.5 ng/gm at 4 and 8 hours), 

#21 (5.6 and 2.9 ng/gm at 2 and 4 hours) and #30 (1.1 ng/gm at 8 hours) dosed with 1 mg/kg 

were noted to have chlorpyrifos in their blood at the assessment times indicated. Subjects #47 

(3.1, 1.3, 3.4 and 1.8 ng/gm at 2, 4, 8 and 12 hours), #49 (3.1 and 1.7 ng/gm at 2 and 8 hours), 

#56 (18.0 and 2.5 ng/gm at 8 and 12 hours) and #59 (2.2, 4.1, 4.1 and 1.5 ng/gm at 2, 4, 8 and 12 

hours) dosed with 2 mg/kg were also shown to have chlorpyrifos in their blood. These are very 

small amounts of chlorpyrifos. The highest level (18 ng/gm) was found in subject #56 at 8 

hours. These data suggest a short half-life for parent chlorpyrifos in blood but there does not 

appear to be sufficient data to establish a firm number for the half-life of chlorpyrifos in the 

blood. 

Blood and urine analysis for the principal metabolite TCP. 

TCP was detected in the blood of all subjects dosed with chlorpyrifos. Refer to 

Appendix Tables. D, E, F, G, and H. 

“The percent recovery corrected for dose as urinary TCP” was reported to be for both 

sexes combined 34.7±19.6%. 30.8±9.9% and 29.5±10.4% for the 0.5, 1 and 2 mg/kg dose 

groups, respectively. (Refer to Table 16 “Estimation of dose Received by Volunteers”, page 47.) 

The extent of absorption is less than the 70% earlier report from Nolan (1984)1 and this 

may be attributed to the fact that the chlorpyrifos in this study was administered in a capsule and 

this would lead to slower absorption. In contrast, in the Nolan study, chlorpyrifos was dissolved 

in methylene chloride and placed on a 0.5-gram lactose tablet, which was swallowed with 100 

mL of water. 

 The half-life of TCP as indicated by the blood and urine data are shown in Table 5. 

Table 5. Half-lives (in hours) based on TCP in the blood and urine. 

Dose 

(mg/kg) 

 Blooda 

Males Females Combined 

 Urineb 

 Males Females Combined 

0.5 29.7±7.4 44.5±32.4 37.1±23.7 29.5±8.9 38.6±24.3 34.3±16.1 

1.0 27.7±5.6 30.5±7.4 29.1±6.4 20.5±5.9 33.6±7.4 31.0±7.3 

 

1 Nolan, R.J. et al, (1984) Chlorpyrifos: Pharmacokinetics in human volunteers. Toxicol. Appl. Pharmacol. 73:8-15. 

 
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2.0 36.2±5.9 35.2±4.8 35.8±5.6 38.1±6.5 32.8±6.5 35.7±6.7 

a. Table 9, page 38. b. Table 15, page 46. 

(Note in MRID 45144101) the printing is small and in some places difficult to distinguish 5, 6 and 8. The best read 

of the number is in Table 5. Since there were only a few and mostly in the standard deviation, these questionable 

numbers should not impact the interpretation.) 

Additional serum TCP data on selected subjects are presented in Table 4. 

Part B. 2. Serum Paraoxonase and chlorpyrifos oxonase (CPOase) Assessment. 

A 5 mL blood sample was taken prior to dosing and sent to the laboratory of Dr. Clement 

Furlong, Department of Medicine and Genetics, University of Washington, Seattle, Washington 

and assessed for paraoxonase activity using a spectrophotometric assay. Paraoxonase was tested 

with chlorpyrifos oxon, paraoxon, or diazoxonase. When the test substance was chlorpyrifos 

oxon, the activity was called CPOase. 

Table 17 of the study report presented data for each subject and group means for the subjects 

dosed in both phase I (October 3, 1998) and II (October 17, 1998). Table 6 summarizes the 

CPOase data in this study. Paraoxonase (range - ~250 to ~2502 units/L, when paraoxon was the 

substrate) and diazoxonase (range ~6548 to 22452 units, when diazinon oxon was the substrate) 

data were also presented but not shown in this review since the subject of the review is 

chlorpyrifos. 

Table 5. CPOase Data 

 Group CPOase Range Comment 

Phase 1 

 Control 8418±1639 5430 to 10410 

56subjects were QQ, 5 were QR. and 1 

was RR. were "QQAow" . Both the high 

and low readings were from OR 

individuals. 

Phase 1 

 0.5 mg/kg 7965±1536 5412 to 13341 

5 were QQ and 7 were QR. The low was 

from a QQ and the high was from a QR. 

Phase 1 

 1 mg/kg 8463±1386 6599 to 11615 

6 were QQ, 5 were QR and 1 was RR. 

The high value was from a QQ and the 

low value was also from a QQ. 

Phase 2 

 Control 11357±3097 6904 to 17333 

6 were QQ and 5 were QR and one was 

RR. The high value was from the RR 

person and the low value was from a QQ 

person. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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22 

 Group CPOase Range Comment 

Phase 2 

 2 mg/kg 9523±1517 7048 to 13018 

6 were QQ, 5 were QR and 1 was RR. 

The high value was from a QR person 

and the low value was also from a QR 

person. 

Subject # 56 has a value of 9278 

Units/liter and is very close to the group 

mean and thus does not have an unusual 

ability to metabolize chlorpyrifos oxon. 

Conclusions, Discussion, Study Deficiencies and Classification. 

1. Study author’s conclusions. 

The study author (page 10 of the study report) concluded "The NOEL for signs and 

symptoms in fasted humans following a single oral dose was 2.0 mg chlorpyrifos/kg of body 

weight. The NOEL for RBC AChE inhibition in humans given a single oral dose of chlorpyrifos 

was 1.0 mg/kg of body weight. The 2.0 mg chlorpyrifos/kg of body weight dose level 

represented a threshold in that it produced greater than 17.3% depression in 1 of 12 volunteers." 

2. Reviewer’s conclusion and discussion. 

Signs and Symptoms. There was no indication that any of the signs and symptoms that 

were noted in the subjects dosed with chlorpyrifos were different in either their nature or degree 

of severity from the signs and symptoms that were noted in the placebo groups. Some reported 

symptoms in the subjects that were dosed with chlorpyrifos occurred either well before or after 

the time when chlorpyrifos absorption was maximal or when the blood or urine level of TCP the 

principal metabolite of chlorpyrifos was at its maximal level. Also, the only subject showing 

definite inhibition of RBC AChE did not display any symptoms when maximum inhibition of 

AChE was attained and this subject's only reported sign (“upper arm numbness”) occurred and 

resolved well before her RBC AChE was shown to be inhibited and before her serum level of 

TCP reached higher levels. If the "upper arm numbness" was related to some other cause due to 

chlorpyrifos than inhibition of RBC AChE it would still be expected for the numbness to persist 

while the absorption of chlorpyrifos increased. Thus, the proposed NOAEL for symptoms is > 2 

mg/kg chlorpyrifos. 

Pharmacokinetic Data. Based on the pattern of occurrence of TCP, the principal 

metabolite of chlorpyrifos in the blood and urine, chlorpyrifos is absorbed rather slowly from the 

gut and requires about 8 to 12 hours for the TCP blood level to reach a maximum. Based on the 

blood level of TCP, subject # 56 absorbed more chlorpyrifos in the first 48 hours than any other 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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23 

subject and this subject also had clear evidence of RBC AChE inhibition. 

The rate and extent of absorption of chlorpyrifos in this study was slower and lower than 

reported in an earlier study (Nolan, 1984), and this was attributed by the study author to be due 

to the differences in administration. In this study, chlorpyrifos was administered in a capsule but 

in the earlier study it was administered on top of a lactose pill. The need for the capsule itself to 

dissolve in the g-I tract may be a factor. 

RBC AChE Inhibition. Review of this study identified one subject (#56, a female dosed 

with 2 mg/kg, with genotype QQ) as demonstrating inhibition of RBC AChE. The decreases in 

RBC AChE were shown to correlate with high levels of TCP in her serum. As much as 28% 

inhibition was noted at 12 hours post dosing. 

A second subject (#51, with genotype OR) was considered as possibly also showing 

inhibition and also had one of the highest levels of serum TCP for the group dosed with 2 mg/kg. 

 Although this subject had decreases to only 5 to 6% of her predosing mean, this level of 

decrease was sustained over the critical hours of expected time for an OP to inhibit blood AChE 

(i.e. 8 to 24 hours). Inspection of the other four females in Phase II indicated that their RBC 

AChE activity was very stable over the 168-hour post dosing period. Overall, subject #51 is 

considered to have only very minimum and indefinite inhibition. 

None of the males were determined to be showing definite decreases in RBC AChE. It 

was noted that one subject (# 48, 2 mg/kg group, OR) had decrease of 8% at 12 hours and 10% 

at 36 hours but two placebo males indicated that variation in RBC AChE activity can also vary 

to a decrease of 10%. Also subject # 48 had one of the lowest net totals of TCP in his blood for 

the group receiving 2 mg/kg. 

Thus, the proposed NOAEL for RBC AChE inhibition is 1 mg/kg and the LOAEL is 2 

mg/kg. Only one female was concluded to have definite inhibition. 

CPOase 

This study has important data on each person's PON and CPOase. The single person 

showing inhibition had CPOase similar to other individuals in the group dosed with 2 mg/kg, but 

this person also had the highest absorption of chlorpyrifos. Thus, the persons ability to absorb 

chlorpyrifos from the gastro-intestinal tract may be more important than the CPOase status of the 

individual. 

Study Classification. 

This study is being classified as RESERVED. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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24 

4. Study deficiencies and compromising issues. 

-Plasma ChE was not assessed for. This is considered important since other recent 

studies with humans and OPs include plasma ChE assessment. Also it was reported in the earlier 

 (Nolan, 1984) study with humans that plasma ChE is inhibited at lower doses than RBC 

AChE by chlorpyrifos. This deficiency is considered a potentially serious omission. 

-The only subject that showed definite inhibition of RBC AChE did not complete the 

study after the 48th hour assessments. This subject did not provide blood samples for 

hematology or clinical chemistry at the scheduled one-week post treatment time. The 

supplementary report (2008, MRID 47436401) indicated that this person was contacted via 

telephone and did not report adverse effects and that she had to leave the study for personal 

reasons. 

-The hematology, clinical chemistry, urinalysis and ECG assessments were made one 

week following the administration of chlorpyrifos. This is considered a poor design. These 

assessments should have been done during the time of peak effect of chlorpyrifos on AChE. 

The assessments after one week are of little value since the chlorpyrifos has been cleared from 

the body and it would be expected that inhibition of AChE would have been partially reversed by 

this time or that the body adapted to the decreased AChE activity. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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 Appendix I - Individual Subject Analysis for subjects showing symptoms or variation in AChE 

Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

Placebo-Males 

 2 

 (no) 

Increased appetite, headache 

(moderate)- vomited. Starting 47 

hrs postdosing, lasting for 4 days, 6 

hrs. Possibly related to treatment. 

"One can coca-cola next day". 

Maximum decrease 12% @ 48 

hrs. Other values are 89% to 

105%. of predose 

 8 

 (yes) 

Headache (mild)- Starting 10 hrs 

postdosing, lasting ~13 hrs. 

Possibly related to treatment.

Maximum decrease 9% @ 48 

hrs. Other values are 94% to 

103%. 

 10 

 (yes) 

No symptoms or events. Maximum decrease 14% @ 96 

hrs. Other values are 88% to 

103%. 

 13 

 (yes) 

No symptoms or events. Maximum decrease 12% @ -10 

hrs. Other values are 97% to 

112%. 

 37 

 (yes) 

Dizzy, feels weak, nausea, vomited, 

body aches - Starting 2 days, 18 hrs 

lasting (some symptoms) for up to 2 

days 11 hrs. Possibly related to 

treatment.

Maximum decrease 3% @ 96 

hrs. Other values 97% to 107% 

of predose. 

 41 

 (no) 

Itching of insect bite. Starting 2 

days 5 hrs, lasting 11 hrs. 

Unrelated to treatment. 

Maximum decrease 7% @ 24 

hrs. Other values 95% ti 107% 

of predose. 

 45 

 (no) 

Nausea, vomited. Starting 2 days. 

Lasting ~20 min. Possibly related 

to treatment.

No decreases. Values are 100 to 

110% of the predose. 

 46 

 (no) 

Headache (mild). Starting ~ 3 hrs. 

Lasting ~ 3hrs. Possibly related to 

treatment.

Maximum decrease 6% @ 2 hrs. 

 Other values 98% to 108% of 

predose. 

Since these subjects are 

in the placebo group, 

there symptoms or 

events cannot be due to 

chlorpyrifos treatment. 

3/12 subjects have headaches. 

4/12 thought they received the chlorpyrifos when it was not given. 

As much as a 14% decrease in RBC AChE can occur within the untreated group over the 7 day period. 

Placebo-Females 

 20 

 (yes) 

No symptoms or events. Maximum decrease 7% at -10 

hrs. Other values 94% to 107%. 

Since these subjects are 

in the placebo group, 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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26 

Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

 23 

 (yes) 

No symptoms or events. Maximum decrease 7% at 144 

hrs. Other values 96 to 110%. 

 29 

 (no) 

“hiccough”, heartburn. Starting 11 

hrs, lasting 11 hrs. Unrelated to 

treatment. 

Maximum decrease 13% at 96 

hrs. Other values 95 to 107%. 

 32 

 (no) 

No symptoms. Maximum decrease 17% and 

sustains from 96 to 144 hrs. 

Other values 85 to 105%. 

Subject included to show 

variation in AChE. 

 50 

 (no) 

Headache (mild)- Starting 1 day 21 

hrs. lasting 3 hrs. Unlikely related 

to treatment. 

Maximum decrease 12% at144 

hrs. Other values 97 to 108% of 

predose. 

 52 

 (yes) 

Headache (mild), loose stool, 

nausea, intestinal cramps, vomited. 

Starting on days 3 and 4, lasting 6-

10 hrs (some symptoms). Possibly 

related to treatment.

Maximum decrease 7% at 24 

hrs. Other values 97 to 103% of 

predose. 

 54 

 (no) 

Headache (moderate and mild), 

nausea. Starting 4-5 hrs, and again 

at 11 hrs. Lasting 6-7 hrs and 17 

hours. Possibly related to 

treatment.

Maximum decrease 4% at 36 

hrs. Other values 97 to 107% of 

predose. 

 60 

 (yes) 

lack of appetite, headache (mild), 

nausea. Starting at 3-5 hrs or 13 

hours. Lasting 5 to 17 hrs. Possibly 

related to treatment.

Maximum decrease 5% at 4 hrs. 

 Other values 97 to 102% of 

predose. 

there reactions cannot 

be due to chlorpyrifos 

treatment. 

4/12 (33%) females had headaches. 

4/12 thought they received the chlorpyrifos when it was not given. 

As much as 17% reduction in RBC AChE can be attained in the untreated female group. 

0.5 mg/kg Chlorpyrifos-Males 

 3 

 (no) 

Increased appetite. Starting 1 day 

and 23 hrs. Lasting 4 days. 

Unlikely related to treatment. 

Maximum decrease 15% at 48 

hrs. Other values 94 to 102% of 

predose. 

Increased appetite is 

not an expected 

response to an OP. Not 

related to treatment 

Maximum decrease not 

supported by earlier or 

later decreases. 

 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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27 

Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

 5 

 (yes) 

Subject implied excessive salivation 

was why he thought he received the 

test material but there were no 

indications of excessive salivation 

listed in the events Table. 

Maximum decrease 8% at 96 

hours. Other values 90 to 

108%. 

No support from either 

the symptoms or AChE 

data to for subjects 

"yes" response. 

 9 

 (no) 

Intestinal cramps. Starting 2 days 

22 hours. Lasting 15 hrs. Unlikely 

related to treatment. 

Maximum decrease 17% at 96 

hrs followed by 11%, 13% and 

9% at 120, 144 and 168 hours. 

Other values Other values were 

87% to 105% of predose. 

Not related to 

treatment since onset 

did not coincide with 

AChE ↓. 

None have headaches. 

1/6 thought they received the chlorpyrifos. 

Note hour 96 had largest decrease in RBC AChE for all but one subject in this group suggesting some assay 

problem. Since it is hour 96, this should not confound the interpretation of the data. 

0.5 mg/kg Chlorpyrifos-Females 

 26 

 (no) 

Nausea. Starting at 1 hr. Lasting 90 

min. Probably related to treatment. 

Maximum decrease 8% at 96, 

144 and 168 hrs. Other values 

are 93% to 104%. 

An initial localized 

nausea may result from 

an OP administration 

in a capsule without 

concomitant ↓in 

AChE. Maximum ↓in 

AChE does not 

coincide with 

symptoms. Not 

considered a definite 

response to 

chlorpyrifos. 

 31 

 (no) 

Headache (moderate). Starting 1 

day and 3 hrs. Lasting ~2 hrs. 

Unlikely related to treatment. 

Maximum decrease 14% at 96 

hrs. Other values were 90% to 

104% of predose. 

Onset of headache does 

not coincide with 

maximum ↓ in AChE 

occurring much later. 

Not related to 

treatment. 

 36 

 (yes) 

Headache (mild), lightheaded, 

headache (mild). Starting 1 hr or 6 

hrs. Lasting ~2 hrs or ~11 hrs. 

Possibly related to treatment. 

Maximum decrease 9% at 4 and 

96 hrs. Other values were 92% 

to 106%. 

Onset of headaches did 

not coincide with 

maximum ↓in AChE. 

2/6 (33%) females had headaches. 

1/6 thought they received the chlorpyrifos. 

Maximum decrease in RBC AChE does not exceed the placebo group. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

1.0 mg/kg chlorpyrifos-Males 

 1 

 (yes) 

Increased appetite. Starting 1 day 

and 23 hrs. Lasting 4 days six hrs. 

Unlikely related to treatment.

Maximum decrease 7% @ 48 

hrs. Other values are 95% to 

113% of predose. 

Symptom not expected 

of an OP exposure and 

does not coincide with 

maximum ↓ AChE. 

 4 

 (yes) 

Loose stool. Starting 2 days and 15-

20 hrs and again on day 4 and 12 

hrs. Lasting 1 min. Unlikely 

related to treatment. 

Maximum decrease 15% @ 96 

hrs followed by deceases of 8%, 

12% and 8% at 120, 144 and 

168 hrs. Other values 90% to 

107%. 

Symptoms do not 

coincide with 

maximum ↓ in AChE. 

 7 

 (yes) 

No symptoms or events. Maximum decrease 16% at 96 

hours. Other values are 91% to 

116%. 

No support for subjects 

"yes" response. 

 11 

 not listed 

Headache (moderate and mild). 

Starting ~3 hrs and again at ~ 23 

hrs. Lasting ~ 19 hrs and 1 day 9 

hrs. Possibly related to treatment. 

Maximum decrease 25% @ 96 

hrs. Other values were 89% (at 

2 hrs) to 101% (at 4 hrs) of 

predose. 

First headache may be 

associated with ~11% 

↓ in AChE. Second 

headache not 

associated with ↓

AChE or maximum 

decrease. 

 14 

 (yes) 

Queasy stomach. Starting 24 min. 

Lasting 10 min. 

Possibly related to treatment.

Maximum decrease 15% @ 144 

hrs. Other values 88% to 99% 

of predose. 

An initial unsettled 

(queasy) stomach may 

result from the capsule. 

 Symptom does not 

coincide with ↓AChE. 

1/6 has a headache. This is less than the placebo group and there is no indication that this subjects headache 

was more severe. 

4/6 thought they received the chlorpyrifos. 

The maximum decrease in this group was in an individual at 96 hrs postdosing. 

1.0 mg/kg Chlorpyrifos-Females 

 24 

 (no) 

Lost voice. Starting ~ 18 hrs. 

Lasting 8 hrs. 

Maximum decrease 11% @ 168 

hrs. Other values 95% to 105% 

of predose. 

Lost voice not an 

expected response to 

an OP. Symptom does 

not coincide with ↓

AChE. Not related to 

treatment. 

 25 

 (yes) 

Tired. Starting ~4 hrs. Lasting 1 

hrs. Possibly related to treatment. 

Maximum decrease 9% @ 96 

and 120 hrs. Other values 92% 

to 102%. 

Symptom does not 

coincide with 

maximum ↓ ACHE. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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29 

Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

Not related to 

treatment. 

 30 

 (no) 

Headache (mild), tired and repeated 

headaches (mild). Starting 22 min, 

~ 2hrs, ~ 10 hrs and ~ 23 hrs. 

lasting. Up to 8 days and 7 hrs. 

Possibly related to treatment.

Maximum decrease 8% @ 96 

hrs. Other values 95% to 109% 

of predose/ 

Onset and duration of 

symptoms so not 

coincide with ↓AChE. 

 

 33 

 (no) 

Headache (mild). Staring ~ 2hrs. 

Lasting 4 hrs. Possibly related to 

treatment.

Maximum decrease 11% @ 144 

hrs. Values from 96 hrs to 168 

hrs were 89% to 955. Other 

values were 97% to 111%. 

Onset of symptom does 

not coincide with 

maximum of any ↓ in 

AChE. 

 35 

 (no) 

Back stiffness. Starting 22 min. 

Lasting ~4 hrs. 

Unlikely related to treatment. 

Maximum decrease 6% @ 168 

hrs. Other values 94% to 115%. 

Symptom not an 

expected response to 

OP treatment and does 

not coincide with 

maximum ↓ AChE. 

Not related to 

treatment. 

2/6 (33%) females had headaches. 

1/6 thought they received the chlorpyrifos. 

Maximum decrease does nor exceed placebo group for RBC AChE. 

2.0 mg/kg Chlorpyrifos-Males 

 40 

 (yes) 

No symptoms or events. Maximum decrease 2% at 48 

hrs. Other values 99% to 103%. 

No support for subjects 

"yes" response. 

 47 

 (no) 

Cut on chin. Starting 2 days. 

Lasting 6 days. Unrelated to 

treatment. 

Maximum decrease 5% at 24 

hrs. Other values 98% to 107% 

of predose. 

Not related to 

treatment. 

None have headache. 

1/6 thought they received the chlorpyrifos. 

Maximum decrease in group was to 10% for one subject (#48 at 36 hours) and dose not exceed the placebo. 

2.0 mg/kg Chlorpyrifos-Females 

 51 

 (yes) 

Headache (mild - moderate). 

Starting at 47 min and again at 3 hrs 

7 min and lasting 2-7 hrs. 

Possibly/probably related to 

treatment. One can coca-cola. 

Maximum decease 6% at 12 hrs. 

 Other values were 95 to 105% 

of the predose. 

Onset of headache does 

not coincide with 

AChE↓. Not related to 

treatment. 

 55 

 (no) 

Headache (mild). Starting 3 hrs, 

lasting 19 hrs. Possibly related to 

Maximum decrease 5% at 120 

hrs. Other values were 97 to 

Onset of headache does 

not coincide with 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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30 

Subject # Symptoms or Events (a) RBC AChE Comments HED’s Conclusion 

treatment. 107% of predose. AChE↓. 

 56 

 not listed 

Numbness in upper arms. Starting 

42 min. Lasting 2 hrs and 24 min. 

Possibly related to treatment.

Maximum decrease 28% at 12 

hrs. ↓ starts at 8 hours 

(23%↓), 

See special discussion. 

 Numbness does not 

coincide with AChE ↓. 

 58 

 (yes) 

No symptoms or events. Maximum decrease 7% at 12 

hrs. Other values are 96% to 

101% 

No support for subjects 

"yes" response. 

 59 

 (yes) 

Tired, headache (mild), chest 

tightness, shortness of breath, 

headache. Starting ~ 2hrs, and 10 

hrs. Lasting 3-13 hrs. Possibly 

related to treatment. 

Maximum decrease 7% at 12 

hrs. Other values were 95% to 

104% of predose. 

First headache does not 

coincide with ↓ AChE, 

the onset of the second 

headache is two hours 

before maximum↓ in 

AChE but ↓ is only 

7%. HED does not

conclude that the 

headache is treatment 

related. 

3/6 (50%) females had headaches. Severity of headache not greater than placebo subjects and onset does not 

coincide with AChE decrease. 

3/6 thought they received the chlorpyrifos. 

One subject has definite inhibition of RBC AChE based on sustained decrease at critical times. 

(a) Only those subjects having reports of symptoms, "events" or responded "yes" (column 1) to 

the question if they thought they received the test material are listed. 

Symptom data are from Appendix 4. Under symptoms, the entry in italics refers to the study 

author’s conclusion regarding whether or not the symptom was related to treatment was made 

before the subjects were identified as to their dose group. 

AChE data are from Table 5.1.2 for phase I and Table 9.1.2 for Phase II. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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Appendix II - List of Tables*

Table A. Mean RBC Cholinesterase Activity (for all groups and all times). 

Table B. Serum Paraoxonase/CPOase and 0-hour RBC AChE Activity and Phenotype for dosed 

groups. 

Table C. Serum Paraoxonase/CPOase and 0-hour RBC AChE Activity and Phenotype for 

control groups. 

Table D. Male RBC AChE Activity, Blood TCP Level and CP Level for the Group Dosed with 

2 mg/kg. 

Table E. Female RBC AChE Activity, Blood TCP Level and CP Level for the Group Dosed 

with 2 mg/kg. 

Table F. Male RBC AChE Activity, Blood TCP Level and CP Level for the Group Dosed with 1 

mg/kg. 

Table G. Female RBC AChE Activity, Blood TCP Level and CP Level for the Group Dosed 

with 1 mg/kg. 

Table H. Male and Female RBC AChE Activity and Blood TCP Level for the Group Dosed with 

0.5 mg/kg. 

Table I. Individual Male and Female RBC AChE Activity (Phase I Control). 

Table J. Individual Male and Female RBC AChE Activity (Phase 2 control) 

Table K. Individual Male and Female Urinary TCP levels. 

* Tables were prepared by Dr. L. Taylor, HED. 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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Table A. Mean RBC Cholinesterase Activity (U/L; mean ± s.d.) 

Time/Dose (mg/kg) 0A 0B 0.5 A 1.0 A 2.0 B

Males 

-10 7520±733 9292±1130 8758±706 9317±790 8802±753 

0 8143±982 9171±1112 8998±730 9572±539 8608±896 

2 8023±795 9282±1026 9145±714 9568±427 8675±844 

4 7948±756 9145±1066 9046±623 9862±865 8642±924 

8 8008±645 9189±1101 9189±924 9524±352 8613±872 

12 8043±705 9198±1003 8848±663 9543±678 8584±806 

24 8036±815 9051±852 9046±817 9599±637 8637±878 

36 7674±556 8999±1020 8716±821 9295±626 8663±937 

48 7505±845 9042±904 8246±896 8694±669 8567±881 

72 7920±838 9425±1041 8974±810 9623±652 9004±840 

96 7421±745 9209±849 8036±738 8263±399 8815±868 

120 7536±694 9337±765 8571±691 8939±255 8807±904 

144 7316±598 9302±800 8764±837 8714±418 8857±907 

168 7770±734 9304±994 8527±764 8600±470 8793±562 

Females 

-10 8488±829 8485±373 8804±1068 8833±597 8503±939 

0 8619±861 8576±556 8612±1160 9165±709 8523±855 

2 8611±915 8444±494 8666±1194 9095±366 8395±855 

4 8762±902 8380±422 8412±1368 9396±517 8557±1181 

8 8817±884 8716±535 8547±1010 9060±528 8230±1274 

12 8404±696 8589±499 8334±917 8886±400 7761±1239 

24 8503±900 8510±667 8434±857 9053±241 8092±1191 

36 8089±829 8399±476 8244±1015 8617±379 8166±1100 

48 8349±735 8545±496 8459±1068 8895±641 8057±1202 

72 8551±583 8941±442 8938±1083 9181±477 8604±1064 

96 7795±759 8620±537 8147±1213 8508±791 8551±812 

120 8092±721 8712±507 8301±857 8466±612 8591±682 

144 8144±872 8428±727 8028±917 8462±714 8526±1111 

168 8036±876 8549±571 8198±910 8366±499 8419±814 

Data from Tables 5.1.1 (pages 55-57) and 9.1.1 (pages 76-77) of MRID 44811002; A Phase 1; B Phase 2 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

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33 

Table B. Serum Paraoxonase/CPOase and 0-hour RBC AChE Activity and Phenotype 

#/phenotype CPOase (U/L) Paraoxonase (U/L) RBC AChE (U/L) 

0.5 mg/kg [range] 

3M (OR) 6850 706 8613 

5M (QQ) 8666 317 7942 

9M (QQ) 10446 417 8602 

12M (QQ) 5412 250 9471 

15M (OR) 6871 745 9889 

18M (OR) 5412 562 9471 

7276±1963 (male) 500±204 (male) 8998±730 (male) 

19F (OR) 8073 595 7282 

22F (OR) 6994 717 9218 

26F (QQ) 8954 373 8602 

28F (OR) 8091 895 9900 

31F (QQ) 6671 261 9515 

36F (OR) 13341 1346 7156 

8687±2424 (female) 698±391 (female) 8612±1160 (female) 

mean±s.d. 7965±1536 (both) 599±315 (both) 

1.0 mg/kg [range] 

1M (QQ) 6599 317 9108 

4M (RR) 8505 1479 9669 

7M (OR) 9008 984 9713 

11M (QQ) 7785 361 10098 

14M (QQ) 8774 367 10087 

16M (OR) 8325 834 8756 

8166±874 (male) 724±464 (male) 9572±539 (male) 

21F (QQ) 11615 467 9900 

24F (QQ) 7534 295 9757 

25F (QQ) 7426 339 9548 

30F (OR) 10141 923 9130 

33F (OR) 8019 1040 8140 

35F (OR) 7821 756 8514 

8754±1719 (female) 637±314 (female) 9165±709 (female) 

mean±s.d. 8463±1386 (both) 680±380 (both) 

2.0 mg/kg [range] 

38M (OR) 13018 1234 8283 

40M (QQ) 8918 345 10021 

42M (OR) 7048 890 9372 

43M (OR) 9134 801 8118 

47M (QQ) 10213 456 7645 

48M (OR) 8199 823 8206 

9422±2051 (male) 758±320 (male) 8608±896 (male) 

49F (QQ) 9997 367 7766 

51F (OR) 10716 1234 7942 

55F (RR) 9422 1590 10076 

56F (QQ) 9278 367 8910 

58F (QQ) 10141 389 8195 

59F (QQ) 8199 345 8250 

9626±871 (female) 715±551 (female) 8523±855 (female) 

mean±s.d. 9523±1517 (both) 737±430 (both) 

pages 48-50, 55-57, and 76-77 (MRID 45144101); QQ (low); OR (mid); RR (high) 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

34 

Table C. Serum Paraoxonase/CPOase and 0-hour RBC AChE Activity (control) and Phenotype 

Subject # CPOase (units/L) Paraoxonase (units/L) RBC AChE (U/L) 

Control [range] 

2M (RR) 9565 1668 9196 

6M (OR) 5430 645 8921 

8M (OR) 6329 728 6809 

10M (OR) 9350 882 7821 

13M (QQ) 7678 317 8833 

17M (QQ) 8001 311 7277 

mean±s.d. 7726±1632 (male) 558±500 (male) 8143±982 (male) 

20F (QQ) 10015 411A 8239 

23F (QQ) 6329 284 8723 

27F (QQ) 8217 350 10208 

29F (OR) 9871 834 7865 

32F (QQ) 9817 434 8723 

34F (OR) 10410 1207 7953 

mean±s.d. 9110±1556 (female) 586±360 (female) 8619±861 (female) 

mean±s.d. 8418±1639 (both) 673±425 (both) 

Control [range] 

37M (OR) 9997 1001 9361 

39M (QQ) 15894 567 8569 

41M (QQ) 9206 378 9592 

44M (OR) 9709 1045 10835 

45M (OR) 11723 1112 7486 

46M (OR) 11363 1134 9185 

mean±s.d. 11315±2445 (male) 872±319 (male) 9171±1112 (male) 

50F (QQ) 10141 423 8492 

52F (QQ) 10069 456 7744 

53F (OR) 14096 1134 8261 

54F (QQ) 6904 289 8602 

57F (RR) 17333 2502 9086 

60F (QQ) 9853 367 9273 

mean±s.d. 11400±3700 (female) 862±860 (female) 8576±556 (female) 

mean±s.d. 11357±3097 (both) 867±618 (both) 

 Pages 57 and 77 (MRID 44811002); QQ (low); OR (mid); RR (high) 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

35 

Table D. Male RBC AChE Activity, Blood TCP Level, and CP Level (2.0 mg/kg) 

Subject # 38 40 42 43 47 48 

Hour AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

9141 

8283 

8437 

8360 

9097 

8800 

8877 

8998 

8481 

9372 

8976 

9108 

8844 

8734 

9680 

10021 

9922 

10109 

9856 

9768 

9790 

9889 

9636 

9966 

9966 

10021 

9955 

9691 

9493 

9372 

9537 

9471 

9152 

9130 

9350 

9405 

9658 

9834 

9648 

9592 

9911 

9174 

8041 

8118 

8206 

7964 

7942 

8327 

8228 

8437 

8129 

8668 

8690 

8052 

8569 

8668 

7887 

7645 

7931 

7942 

7744 

7788 

7370 

7700 

7667 

8107 

7942 

8305 

7920 

8305 

8569 

8206 

8019 

8008 

7887 

7689 

8206 

7546 

7832 

8074 

7766 

7766 

7942 

8184 

Chlorpyrifos concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

3.1 

1.3 

3.4 

1.8 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

TCP concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

420 

560 

510 

440 

430 

500 

530 

1100

290 

160 

85 

41 

ND 

61 

220 

320 

340 

340 

360 

410 

270 

170 

120 

75 

98 

ND 

44 

130 

230 

270 

ns 

360 

370 

320 

220 

160 

96 

220 

ND 

230 

340 

330 

410 

520 

610 

610 

320 

190 

90 

66 

40 

ND 

580 

640 

790 

910 

980 

960 

1000 

690 

460 

320 

220 

150 

ND 

180 

250 

240 

260 

380 

460 

470 

300 

210 

140 

77 

48 

Data from Tables 5 and 7 (pages 34 and 36) of MRID 45144101; ns no sample; value not used
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

36 

Table E. Female RBC AChE Activity, Blood TCP Level and CP Level (2 mg/kg) 

Subject # 49 51 55 56 58 59 

hours AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

7832 

7766 

7700 

7662 

8008 

7513 

8008 

8710 

7568 

7920 

7986 

8019 

7931 

8327 

8283 

7942 

7931 

7997 

7986 

7640 

7722 

7700 

7876 

8195 

8415 

8569 

7975 

8074 

10373 

10076 

10032 

10901 

10582 

10032 

10131 

10274 

10395 

10461 

9933 

9757 

10472 

9845 

8426 

8910 

8602 

8525 

6688 (25) 

6221 (30) 

6424 (28) 

7051 (21) 

6892 (23) 

X 

X 

X 

X 

X 

8041 

8195 

8041 

8096 

7931 

7535 (8) 

8107 

8107 

7821 

8503 

7931 

8228 

7832 

7876 

8063 

8250 

8063 

8162 

8184 

7623 (8) 

8162 

8052 

7788 

7942 

8492 

8382 

8415 

7975 

Chlorpyrifos concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

0168 

ND 

3.1 

xx 

1.7 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

18.0 

2.5 

ND 

ND 

ND 

X 

X 

X 

X 

X 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

2.2 

4.1 

4.1 

1.5 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

TCP concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

290 

450 

490 

440 

470 

430 

360 

200 

130 

84 

52 

35 

ND 

420 

580 

1300 

690 

540 

750 

730 

600 

420 

150 

170 

110 

ND 

290 

220 

520 

500 

600 

600 

530 

340 

210 

120 

73 

45 

ND 

71 

120 

1600 

1500 

1300 

1100 

980 

X 

X 

X 

X 

X 

ND 

240 

310 

480 

340 

400 

430 

360 

190 

110 

65 

37 

24 

ND 

250 

470 

610 

610 

500 

480 

390 

220 

110 

58 

32 

23 

Data from Tables 5 and 7 (pages 34 and 36) of MRID 45144101; (% inhibition from 0 hour); xx sample not analyzed; X subject 

left study 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

37 

Table F. Male RBC AChE Activity, Blood TCP Level and CP Level (1.0 mg/kg) 

Subject # 1 4 7 11 14 16 

AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

8272 

9108 

9625 

9823 

9284 

9042 

9306 

9119 

8074 

9295 

8283 

9218 

8833 

8228 

9416 

9669 

9438 

9405 

9361 

10219 

10219 

9702 

8624 

10164 

8151 

8723 

8426 

8734 

9603 

9713 

10230 

11198 

9834 

10109 

9966 

9746 

9196 

9801 

8096 

8800 

9141 

9174 

10307 

10098 

9097 

10318 

9768 

9779 

9977 

9768 

9141 

10153 

7700 (↓24) 

9185 

9218 

- 

9823 

10087 

9845 

9801 

9878 

9658 

9658 

9295 

9174 

9867 

8899 

9086 

8492 

8844 

8481 

8756 

9174 

8624 

9020 

8448 

8470 

8140 

7953 

8459 

8448 

8624 

8173 

8019 

Chlorpyrifos concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

Ns 

1.0 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

Ns 

ND 

ND 

2.7 

1.5 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

TCP concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

140 

280 

340 

340 

440 

430 

310 

160 

84 

41 

18 

11 

ND 

49 

130 

290 

300 

250 

240 

230 

160 

98 

54 

34 

20 

ND 

370 

430 

440 

350 

270 

160 

140 

54 

23 

10 

ND 

ND 

ND 

260 

450 

400 

340 

270 

200 

160 

75 

36 

20 

ND 

Ns 

ND 

170 

570 

610 

540 

520 

440 

420 

280 

220 

150 

84 

50 

ND 

150 

200 

170 

170 

200 

280 

300 

210 

130 

84 

48 

29 

Data from page 56 of 578 and Tables 5 and 7 (pages 34 and 36) of MRID 45144101; ns no sample; 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

38 

\\ Table G. Female RBC AChE Activity, Blood TCP Level and CP Level (1.0 mg/kg) 

Subject # 21 24 25 30 33 35 

AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

9416 

9900 

9460 

10087 

9394 

9361 

9317 

8789 

9361 

9064 

8637 

8954 

8932 

8624 

9295 

9757 

9460 

9999 

9570 

9350 

9097 

9218 

9604 

9240 

8844 

9086 

9207 

8525 

9031 

9548 

9240 

9152 

9427 

8855 

9339 

8624 

9174 

9460 

8437 

8426 

8580 

8855 

9064 

9130 

8932 

9229 

9119 

8822 

8943 

8536 

8998 

9900 

8349 

8855 

8613 

8712 

7942 

8140 

8965 

8866 

8624 

8470 

8877 

8074 

7766 

8503 

7178 

7601 

7156 

7678 

8250 

8514 

8514 

9042 

8228 

8459 

8745 

8459 

8569 

8921 

9603 

7876 

8283 

7799 

Chlorpyrifos concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

5.6 

2.9 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

1.1 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

2ND 

1ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

ND 

 ND 

ND 

ND 

ND 

TCP concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

220 

350 

310 

300 

300 

290 

280 

140 

75 

43 

22 

13 

ND 

96 

430 

340 

310 

320 

320 

300 

250 

180 

120 

73 

47 

ND 

160 

180 

190 

190 

220 

200 

160 

85 

30 

16 

ND 

ND 

ND 

10 

160 

310 

290 

290 

280 

280 

240 

160 

85 

45 

23 

ND 

32 

93 

100 

110 

140 

140 

110 

70 

45 

29 

17 

13 

ND 

72 

250 

490 

430 

370 

310 

350 

190 

140 

99 

75 

30 

Data from page 56 of 578 and Tables 5 and 7 (pages 34 and 36) of MRID 45144101; ns no sample; 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

39 

Table H. Male and Female RBC AChE Activity and Blood TCP Level (0.5 mg/kg) 

Subject # 3 5 9 12 15 18 

MALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

8393 

8613 

8668 

8514 

8228 

8118 

8393 

7997 

7244 

8426 

8558 

8679 

8283 

8107 

7865 

7942 

8547 

8481 

8217 

8030 

8074 

7810 

7128 

8074 

7282 

7920 

8712 

7931 

8294 

8602 

8437 

8646 

8844 

8723 

8580 

8261 

8107 

8260 

6985 (↓19) 

7535 (↓12) 

7376 (↓14) 

7700 (↓11) 

8877 

9471 

9218 

9031 

9482 

9229 

9394 

8910 

9053 

9504 

8096 

8921 

9537 

8547 

9713 

9889 

10021 

9944 

9845 

9471 

9680 

9670 

9119 

9889 

8525 

9207 

9548 

9295 

9405 

9471 

9977 

9658 

10516 

9515 

10153 

9746 

8822 

9702 

8767 

9163 

9130 

9581 

MALES TCP concentrations (ng/g) in blood samples 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

ND 

23 

95 

97 

96 

130 

140 

140 

87 

58 

38 

22 

14 

ND 

49 

53 

51 

130 

98 

100 

100 

59 

24 

8 

ND 

ND 

ND 

24 

140 

130 

240 

130 

130 

120 

70 

41 

25 

14 

10 

ND 

29 

83 

96 

97 

100 

110 

110 

96 

67 

38 

19+ 

ND 

ND 

160 

250 

240 

210 

190 

190 

190 

130 

88 

56 

33 

23 

ND 

51 

100 

130 

130 

120 

110 

110 

73 

48 

29 

15 

9 

Subject # 19 22 26 28 31 36 

FEMALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

9724 

7282 

7986 

7810 

8041 

7843 

7832 

7535 

7623 

7953 

7997 

7931 

7689 

7744 

9086 

9218 

8932 

9141 

9097 

8349 

8866 

8987 

8921 

9394 

8646 

8437 

8195 

8657 

8063 

8602 

8448 

8239 

8305 

8437 

8041 

7810 

8129 

8701 

7689 

7975 

7744 

7733 

10010 

9900 

10252 

10593 

9966 

9779 

9746 

9834 

10109 

10516 

10153 

9581 

9218 

9130 

8800 

9515 

9526 

8239 

8866 

8602 

8756 

8228 

8855 

9482 

7920 

8811 

8734 

9086 

7139 

7156 

6853 

6501 

7007 

6996 

7365 

7068 

7117 

7579 

6474 

7073 

6589 

6837 

FEMALES TCP concentrations (ng/g) in blood samples

0 

2 

4 

8 

12 

24 

36 

48 

72 

ND 

110 

190 

210 

ND 

189 

179 

180 

110 

ND 

190 

380 

350 

310 

220 

150 

140 

59 

ND 

12 

89 

110 

110 

130 

190 

180 

160 

ND 

61 

91 

140 

130 

140 

110 

91 

46 

ND 

77 

120 

220 

230 

210 

200 

190 

130 

ND 

62 

220 

260 

230 

220 

230 

230 

150 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

40 

96 

120 

144 

168 

88 

58 

35 

23 

31 

17 

ND 

ND 

140 

120 

107 

88 

25 

14 

ND 

ND 

64 

41 

22 

14 

83 

49 

27 

19 

Data from Tables 5 and 7 (pages 34 and 36) of MRID 45144101 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

41 

Table I. Male and Female RBC AChE Activity (Phase 1 control) 

Subject # 2 6 8 10 13 17 

MALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

8294 

9196 

8910 

8382 

8239 

8360 

8734 

8448 

7711 

8569 

8151 

8404 

7810 

8206 

7810 

8921 

8558 

8580 

8701 

8635 

8723 

7700 

7964 

8921 

7536 

7799 

7733 

8778 

6562 

6809 

6782 

6622 

6886 

6886 

6655 

6864 

6083 

6672 

6336 

6457 

6281 

6677 

8327 

7821 

8019 

8118 

7986 

7876 

8426 

8052 

7678 

7920 

6771 

7321 

7134 

7623 

6985 

8833 

8448 

8481 

8481 

8789 

8173 

7689 

8536 

8195 

8206 

8041 

7799 

8019 

7139 

7277 

7420 

7502 

7755 

7711 

7502 

7288 

7057 

7244 

7524 

7194 

7139 

7315 

Subject # 20 23 27 29 32 34 

FEMALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

7178 

8239 

7568 

7953 

8239 

7898 

7645 

7249 

7931 

7843 

7415 

7513 

7722 

7689 

8481 

8723 

9053 

9504 

9174 

8657 

8844 

8712 

8800 

8789 

8272 

8360 

7975 

8437 

9724 

10208 

10010 

10076 

10373 

9713 

10098 

9284 

9603 

9416 

8800 

9053 

9570 

9317 

8382 

7865 

8382 

8426 

8701 

8118 

8195 

7843 

8184 

8437 

7073 

8283 

8206 

7722 

8294 

8723 

8932 

8855 

8569 

8085 

8481 

8261 

8008 

8822 

8305 

- 

- 

- 

8866 

7953 

7722 

7755 

7843 

7953 

7755 

7183 

7568 

7997 

7002 

7249 

7249 

7013 

Data from Table 5.1.1 (pages 57) of MRID 44811002 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

42 

Table J. Male and Female RBC AChE Activity (Phase 2 control) 

Subject # 37 39 41 44 45 46 

MALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

9878 

9361 

9394 

9757 

10318 

9999 

9680 

9669 

9713 

9482 

9306 

9427 

9416 

9823 

8910 

8569 

8723 

8470 

8382 

8723 

8547 

8294 

8481 

8657 

8778 

8976 

8811 

8437 

9240 

9592 

10197 

9240 

8998 

8998 

8789 

8910 

9119 

9394 

9460 

9504 

9174 

9548 

10769 

10835 

10681 

10703 

10494 

10164 

10197 

10318 

10208 

10923 

10329 

10406 

9691 

10802 

7387 

7486 

7898 

7590 

7645 

7613 

7810 

7453 

7645 

7975 

7810 

8096 

8184 

8041 

9570 

9185 

8800 

9108 

9295 

9790 

9284 

9350 

9086 

10120 

9570 

9614 

10538 

9174 

Subject # 50 52 53 54 57 60 

FEMALES AChE (U/L) 

-10 

0 

2 

4 

8 

12 

24 

36 

48 

72 

96 

120 

144 

168 

8107 

8492 

8327 

8239 

8415 

8404 

8415 

8063 

8184 

9108 

8426 

8965 

7337 

8382 

7975 

7744 

7623 

7645 

7865 

7854 

7293 

7810 

7854 

8096 

7623 

7810 

7854 

7634 

8712 

8261 

8547 

8349 

9031 

8723 

8756 

8470 

8844 

9273 

8811 

8569 

9339 

8591 

8470 

8602 

8294 

8558 

8558 

8327 

8437 

8228 

8327 

9108 

9108 

8646 

8415 

8382 

8734 

9086 

9020 

8866 

9218 

8987 

9174 

8668 

8954 

9229 

8899 

9229 

8778 

9086 

8910 

9273 

8855 

8624 

9207 

9240 

8987 

9152 

9108 

8833 

8855 

9053 

8844 

9218 

Data from Table 9.1.1 (pages 77) of MRID 44811002 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

43 

Table K1. Male and Female Urine TCP Level (0.5 mg/kg) 

Subject # 3 (QR) 5 (QQ) 9 (QQ) 12 (QQ) 15 (QR) 18 (QR) 

Time interval (hr) MALES TCP concentrations (ng/mL) in urine samples 

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

BLOQ 

98 

593 

964 

636 

981 

1103 

636 

496 

278 

178 

120 

148 

161 

98 

70 

3.4 

520 

724 

907 

1440 

739 

298 

453 

360 

70 

140 

63 

44 

9 

9.3 

5.8 

4.4 

1396 

1217 

940 

1512 

1472 

1108 

94.5 

600 

316 

146 

223 

96 

56 

11.4 

11 

BLOQ 

152 

427 

678 

712 

1239 

1398 

959 

680 

422 

345 

464 

211 

115 

122 

110 

3.4 

417 

1256 

1256 

687 

ns 

ns 

1389 

465 

ns 

112 

315 

ns 

190 

ns 

91 

7.1 

200 

482 

1388 

836 

1688 

1605 

690 

500 

366 

298 

184 

196 

136 

137 

78 

Subject # 19 22 26 28 31 36 

FEMALES TCP concentrations (ng/mL) in urine samples

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

19 

618 

1292 

4292 

2065 

974 

1972 

2973 

ns 

919 

714 

688 

ns 

711 

ns 

132 

BLOQ 

1369 

719 

1578 

490 

755 

673 

597 

359 

159 

96 

112 

38 

12 

84 

24 

5.2 

284 

344 

2057 

716 

805 

2012 

653 

691 

1530 

1090 

1107 

356 

1754 

1502 

504 

4.5 

500 

238 

509 

360 

366 

162 

200 

66 

115 

50 

75 

41 

29 

22 

46 

BLOQ 

347 

393 

730 

365 

590 

169 

384 

230 

234 

57 

100 

42 

62 

26 

42 

2.4 

622 

468 

608 

671 

726 

232 

362 

514 

246 

554 

276 

130 

158 

161 

98 

Data from Appendix Table 3 (pages 68 -70) of MRID 45144101; ns no sample; 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

44 

 Table K2. Male and Female Urine TCP Level (1.0 mg/kg) 

Subject # 1 (QQ) 4 (RR) 7 (QR) 11 (QQ) 14 (QQ) 16 (QR) 

Time interval (hr) MALES TCP concentrations (ng/mL) in urine samples 

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

3.4 

496 

1373 

3217 

2224 

2896 

928 

1414 

889 

816 

321 

142 

220 

268 

134 

74 

5 

212 

1779 

1636 

2034 

1334 

2520 

974 

502 

1169 

690 

807 

308 

462 

362 

70 

3.2 

1286 

2499 

2941 

3706 

1126 

845 

306 

107 

142 

51 

44 

9 

20 

8 

8 

5.3 

2128 

2764 

4758 

1967 

3109 

ns 

1790 

ns 

390 

ns 

174 

ns 

98 

ns 

ns 

8.8 

4496 

7952 

3602 

3382 

4526 

2900 

3202 

2976 

2455 

ns 

808 

1254 

1216 

1137 

568 

3.4 

1614 

658 

716 

3666 

2370 

2486 

759 

1579 

1301 

1418 

590 

1304 

299 

360 

231 

Subject # 21 (QQ) 24 (QQ) 25 (QQ) 30 (QR) 33 (QR) 35 (QR) 

Time interval (hr) FEMALES TCP concentrations (ng/mL) in urine samples

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

6.4 

517 

2859 

2402 

1240 

2593 

3114 

716 

1351 

1885 

402 

550 

280 

264 

52 

184 

2.8 

1126 

1784 

1302 

1744 

2054 

1533 

1193 

1626 

1308 

466 

1027 

455 

300 

136 

220 

2.8 

808 

1422 

1472 

2341 

740 

1118 

792 

706 

426 

218 

192 

140 

76 

56 

48 

7.2 

722 

3332 

1914 

2515 

2642 

2228 

1562 

1848 

1148 

1091 

1131 

894 

766 

592 

556 

12.8 

169 

737 

1278 

852 

1289 

ns 

752 

574 

598 

402 

352 

ns 

336 

168 

204 

BLOQ 

390 

466 

935 

451 

806 

324 

424 

404 

191 

216 

142 

161 

110 

98 

49 

Data from Appendix Table 4 (pages 71 -73) of MRID 45144101; ns no sample; 
Chlorpyrifos/P. C. Code 059101 DRAFT 5/27/09 Special RBC AChE Inhibition Study (1999)

Humans 

 (non-guideline) 

45 

Table K3. Male and Female Urine TCP Level (2.0 mg/kg) 

Subject # 38 (QR) 40 (QQ) 42 (QR) 43 (QR) 47 (QQ) 48 (QR) 

Time interval (hr) MALES TCP concentrations (ng/mL) in urine samples 

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

4.8 

1308 

2030 

2794 

3263 

2822 

2674 

2216 

1318 

1656 

900 

542 

501 

464 

507 

414 

BLOQ 

189 

578 

2224 

1196 

1931 

1218 

730 

560 

371 

572 

454 

184 

185 

170 

264 

BLOQ 

878 

3282 

6164 

4532 

2818 

3458 

1213 

ns 

1556 

ns 

2398 

1507 

622 

1707 

994 

8.4 

850 

1314 

2672 

5188 

5725 

1688 

2344 

1126 

1618 

886 

870 

747 

794 

659 

402 

7 

1506 

4704 

15323 

5549 

8610 

8865 

8129 

5416 

3905 

2444 

2342 

1298 

1512 

1482 

- 

3.0 

949 

784 

3360 

3262 

2662 

853 

1848 

752 

659 

427 

722 

428 

642 

452 

- 

Subject # 49 (QQ) 51 (QR) 55 (RR) 56 (QQ) 58 (QQ) 59 (QQ) 

Time interval (hr) FEMALES TCP concentrations (ng/mL) in urine samples

-12-0 

0-6 

6-12 

12-24 

24-36 

36-48 

48-60 

60-72 

72-84 

84-96 

96-108 

108-120 

120-132 

132-144 

144-156 

156-168 

4.4 

882 

2183 

3310 

1453 

1897 

958 

1130 

645 

570 

218 

286 

226 

288 

150 

133 

10.9 

1413 

3688 

6064 

1786 

3736 

2114 

1443 

1286 

2526 

1078 

1014 

918 

474 

696 

616 

5.1 

676 

1850 

5275 

1658 

4537 

1662 

2548 

533 

354 

332 

448 

206 

329 

212 

98 

10.9 

1246 

7966 

8148 

6270 

7068 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

4.5 

1690 

994 

1868 

2304 

2458 

1538 

1469 

1496 

1530 

604 

631 

84 

85 

182 

147 

4.2 

1881 

4682 

5036 

6622 

3822 

2902 

2370 

1855 

1198 

842 

1113 

805 

636 

228 

156 

Data from Appendix Table 5 (pages 74 -76) of MRID 45144101; ns no sample;