**DATA EVALUATION RECORD**

**OXAMYL/103801**

**NON-GUIDELINE STUDY**

**STUDY TYPE: ASCENDING ORAL TOXICITY STUDY IN HUMANS**

**MRID 44912301**

Prepared for

Health Effects Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

1801 Bell Street

Arlington, VA 22202

Prepared by

Toxicology and Hazard Assessment Group

Life Sciences Division

Oak Ridge National Laboratory

Oak Ridge, TN 37831

Task Order No. 74-2005

Primary Reviewer:

[Judith H. Moyer, Ph.D., D.A.B.T.]{.underline} Signature:

Date:

Secondary Reviewers:

> Signature:

[Sylvia Milanez, Ph.D., D.A.B.T.]{.underline} Date:

[Robert H. Ross, M.S., Group Leader]{.underline} Signature:

Date:

Quality Assurance:

[Lee Ann Wilson, M.A.]{.underline} Signature:

Date:

Disclaimer

This review may have been altered subsequent to the contractors'
signatures above.

Oak Ridge National Laboratory managed and operated by UT-Battelle, LLC.,
for the U.S. Department of Energy under Contract No. DE-AC05-00OR22725.

**EPA Reviewer:** [Elissa Reaves, Ph.D.]{.underline} **Signature**:

**Reregistration Branch 2, Health Effects Division (7509C)** **Date**

**EPA Secondary Reviewer**: [Anna Lowit, Ph.D.]{.underline}
**Signature**:

**Reregistration Branch 2, Health Effects Division (7509C)** **Date**

Template version 11/01

**[TXR#]{.underline}:** 0052872

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  **DATA EVALUATION RECORD**

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**[STUDY TYPE]{.underline}:** Ascending Oral Toxicity - Humans,
non-guideline.

**[PC CODE]{.underline}:** 103801 **[DP BARCODE]{.underline}:** 308714

**[TEST MATERIAL (PURITY)]{.underline}:** Ethanimidothioic acid,
2-(dimethylamino)-N{\[(methlamino)carbonyl\]oxy}\]-2-oxo, methyl ester
(97.6%)

**[SYNONYMS]{.underline}:** Oxamyl technical, DPX-D1410 Technical,
Methyl
2-(dimethylamino)-N-\[(methylamino)carbonyl)oxy)-2-oxo-ethanimidothioate,
Methyl N',N'-dimethyl-N-\[(methyl carbonyl)oxythiooxaminidate

**[CITATION]{.underline}:** McFarlane, P., Freestone, S. (1999) A
randomized double blind ascending oral dose study with oxamyl. Inveresk
Clinical Research, Riccarton, Edinburgh, EH14 4AP, Scotland. Laboratory
Project ID: HLO-1998-01505, August 10, 1999. MRID 44912301. Unpublished.

**[SPONSOR]{.underline}:** E.I. du Pont de Nemours and Company, Newark,
Delaware 19714-0050

**[EXECUTIVE SUMMARY]{.underline}:** In a non-guideline, ascending acute
oral toxicity study (MRID 44912301), 40 healthy human male volunteers,
aged 19 - 39 years, were each given a single oral dose of oxamyl
technical (approximately 97.6% a.i., batch #: DPX-D140-196) in a gelatin
capsule at doses of 0, 0.005, 0.015, 0.03, 0.06, 0.09, or 0.15 a.i.
mg/kg bw. Volunteers were admitted to the clinic the afternoon prior to
the morning dosing. The volunteers were fasted for 9 hours prior to
breakfast. Study volunteers were dosed approximately 5 minutes following
a "standard" breakfast, and observed for two nights and one follow-up
visit 7 ( 2) days post-dose. All volunteers remained under close medical
and nursing supervision throughout the study. The study was conducted as
a double-blind ascending-dose escalation clinical trial, and each male
was treated at one of nine dosing sessions. Volunteers received a
complete screening physical examination, testing for Hepatitis B, C, and
HIV infection, and drug-screening of urine within 14 days of study
commencement. Blood pressure and heart rate were measured at screening
(within 14 days prior to dosing), 16 hours pre-dose (admission), 30
minutes pre-dose, and 1, 2, 3, 4, 8 ,and 24 hours post-dose. Oral
temperature was recorded at screening, 16 hours and 30 minutes pre-dose,
and 2, 4, and 24 hours post-dose. A 12-lead ECG was obtained at
screening, 30 minutes pre-dose, and 30 minutes, 1, 2, and 24 hours
post-dose. Hematology and clinical chemistry testing was performed at
screening, 30 minutes pre-dose, and 24 hours post-dose. Urinalysis was
conducted at screening and 24 hours post-dose. Pupillometry was
performed 16 hours and 30 minutes pre-dose, and 1, 2, 3, 4, 8, and 24
hours post-dose. Saliva was collected and quantified by weight 16 hours
and 30 minutes pre-dose, and 1, 2, 3, 4, 8, and 24 hours post-dose.
Plasma and red blood cell cholinesterase activity were assayed at
screening, and 2 days, 16 hours, and 30- minutes pre-dose, and at 0.25,
0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours
post-dose, and at 7 ( 2) days post-dose.

Clinical signs were reported by a total of 7 individuals from both the
placebo (3 volunteers) and oxamyl dose groups (4 volunteers). These
clinical observations did not correspond with peak ChE inhibition and
were therefore not considered to be treatment related. Clinical
observations from the placebo volunteers included bleeding gums,
headache, fever, tremor, muscular pains, and right sided groin pain.
Symptoms reported by the two volunteers in the 0.015 mg/kg dose group
included headache (pre-dose), brief nausea (57 minutes post-dose to 61
minutes), and abdominal pain (46 hours post-dose to 46.5 hours
post-dose). Examination of the volunteer with the brief nausea revealed
no inhibition of cholinesterase activity or effects on pupil size or
salivation and so was deemed unlikely related to the test compound. An
earache was noted by one volunteer (46 hours post-dose to 46.5 hours
post-dose) of the 0.03 mg/kg dose group. At 0.15 mg/kg, one volunteer
experienced a headache (6 hours 50 minutes lasting 15 hours 15 minutes)
and increased generalized sweating (10 hours 50 minutes lasting 3 hours
55 minutes). Both of these symptoms were considered possibly related to
study compound but further investigation revealed the time course of
symptoms were not consistent with the cholinesterase activity inhibition
observed. Therefore, the adverse events were not likely to be truly
related to the test compound.

The mean percent change in plasma cholinesterase activity was
statistically decreased compared to placebo in the high dose (0.15
mg/kg) beginning at the first time point (-14%, 15 min) until 3 hours
post-dosing (-8%), with peak inhibition at 45 minutes post-dosing (43%,
p\<0.001). Plasma cholinesterase activity returned to baseline by 6
hours post-dosing. For the group exposed to 0.09 mg/kg, plasma
cholinesterase activity was significantly inhibited starting at 75
minutes post-dosing (-12% peak, p=0.026) until 2 hours post-dosing
(-10%, p=0.039) with recovery at 3 hours post-dosing. Within the 0.06
mg/kg dose group, the maximum plasma cholinesterase inhibition was -7%
at 75 minutes post-dosing (non-statistical, p=0.22). Plasma
cholinesterase activity was similar to placebo in the 0.005, 0.015 and
0.03 mg/kg dose groups at all time points. However, when the linear
trend was tested for dose at each time point, the test was significant
for every time point except at 4, 8, 12, and 24 hours, and 7 days
post-dosing. The inclusion or exclusion of outlying values did not alter
the results for plasma cholinesterase activity.

The mean RBC cholinesterase activity of the high dose group (0.15 mg/kg)
was inhibited significantly beginning at 30 minutes (-23%, p\<0.001)
with peak inhibition at 45 and 60 minutes (-28% and -27%, respectively
with p\<0.001 for both) until 2 hours post-dosing (-8%, p=0.011) and
recovery to baseline by 3 hours post-dosing. For the 0.09 mg/kg dose
group, the mean RBC cholinesterase activity was significantly decreased
only at 30 minutes (-7%, p=0.016) with recovery following at 45 minutes
post-dosing. RBC cholinesterase activity was statistically similar to
placebo at all time points in the 0.005, 0.015, 0.03, and 0.06 mg/kg
dose groups. Analysis of a linear trend for RBC cholinesterase activity
by dose at varying time points indicated significance from 30 minutes
until 105 minutes post-dosing.

Saliva weight when examined with outliers was increased in the two
highest dose groups at 1 hour post-dosing compared to the placebo group.
A linear trend was observed for saliva weight (change from baseline),
which increased with increasing dose and was only significant (p=0.002)
at the 1 hour time point. The significance of saliva weight and dose was
not achieved at any other time point during the study.

There were no significant decreases in minimum pupil size and recovery
pupil size relative to baseline between any dose level and placebo, at
any of the time points. Significant increases in recovery pupil size
were observed at 2,4, 8 and 24 hour post-dosing in the 0.005 mg/kg group
when compared to placebo. However, increases in pupil size are contrary
to the expected response to cholinergic stimulation by the test
substance.

**Under the conditions of this ascending oral dose study in humans, 0.09
mg/kg/day represents a level where 7-12% plasma and RBC ChE inhibition
was observed. Three of 5 volunteers at this dose (0.09 mg/kg/day)
exhibited greater than 20% plasma ChE inhibition. Therefore, 0.06
mg/kg/day is considered the NOAEL.**

The Agency generated BMD and BMDL estimates based on the RBC ChE data
from this study. The resulting RBC BMD~10~ is 0.083 mg/kg with BMDL~10~
of 0.069 mg/kg.

**[COMPLIANCE]{.underline}:** Signed and dated Good Clinical Practice
Compliance, Quality Assurance, and No Data Confidentiality statements
were provided. The study was conducted in accordance with the
Declaration of Helsinki, 1964, as amended by the 29^th^ Medical World
Assembly in Tokyo (1975), the 35^th^ Medical World Assembly in Venice,
1983, 41^st^ Medical World Assembly in Hong Kong, 1989, and the 48^th^
General Assembly, Somerset West, Republic of South Africa, October 1996.

**I. MATERIALS AND METHODS**

**A. [MATERIALS]{.underline}:**

  -------------------------- ------------------ ----------------------------------------------------
  **1. [Test                                    Oxamyl technical
  Material]{.underline}:**                      

                             **Description:**   White solid; "appeared to be stable" under study
                                                conditions. Analyses were conducted to assess the
                                                accuracy, homogeneity and stability of the
                                                preparation prior to the initiation of dosing

                             **Lot/Batch #:**   Batch No. DPX-D1410-196

                             **Purity:**        Approx. 97.6% a.i., approx. 2.25% inerts. .

                             **CAS \# of        23135-22-0
                             TGAI:**            

                             **Chemical         ![](media/image1.png)
                             structure:**       
  -------------------------- ------------------ ----------------------------------------------------

**2. [Vehicle and/or positive control]{.underline}:** Oxamyl technical
was administered in a gelatin capsule as an oxamyl/lactose blend.
Placebo was lactose administered in a matching capsule.

+---+--------------+----------+----------------------------------------+
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| } |              |          |                                        |
| : |              |          |                                        |
| * |              |          |                                        |
| * |              |          |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Species:** | Human    |                                        |
|   |              | (Male)   |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Strain:**  | N.A.     |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Age/weight | Age:     |                                        |
|   | at dosing:** | 19 - 39  |                                        |
|   |              | years;   |                                        |
|   |              | Weight:  |                                        |
|   |              | 60.8 -   |                                        |
|   |              | 95.5 kg  |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Source:**  | Vo       |                                        |
|   |              | lunteers |                                        |
|   |              | r        |                                        |
|   |              | ecruited |                                        |
|   |              | and      |                                        |
|   |              | screened |                                        |
|   |              | for      |                                        |
|   |              | i        |                                        |
|   |              | nclusion |                                        |
|   |              | in the   |                                        |
|   |              | study by |                                        |
|   |              | Inveresk |                                        |
|   |              | Clinical |                                        |
|   |              | Research |                                        |
|   |              | clinical |                                        |
|   |              | staff.   |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Housing:** | Admitted |                                        |
|   |              | to       |                                        |
|   |              | clinic   |                                        |
|   |              | the      |                                        |
|   |              | a        |                                        |
|   |              | fternoon |                                        |
|   |              | prior to |                                        |
|   |              | morning  |                                        |
|   |              | dosing,  |                                        |
|   |              | and      |                                        |
|   |              | di       |                                        |
|   |              | scharged |                                        |
|   |              | approx.  |                                        |
|   |              | 24 hours |                                        |
|   |              | po       |                                        |
|   |              | st-dose. |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Diet:**    | "S       |                                        |
|   |              | tandard" |                                        |
|   |              | b        |                                        |
|   |              | reakfast |                                        |
|   |              | approx.  |                                        |
|   |              | 5        |                                        |
|   |              | minutes  |                                        |
|   |              | before   |                                        |
|   |              | dosing;  |                                        |
|   |              | fasted   |                                        |
|   |              | until    |                                        |
|   |              | approx.  |                                        |
|   |              | 3 hours  |                                        |
|   |              | p        |                                        |
|   |              | ost-dose |                                        |
|   |              | and then |                                        |
|   |              | allowed  |                                        |
|   |              | decaf    |                                        |
|   |              | feinated |                                        |
|   |              | fluids;  |                                        |
|   |              | and a    |                                        |
|   |              | light    |                                        |
|   |              | lunch    |                                        |
|   |              | approx.  |                                        |
|   |              | 4 hours  |                                        |
|   |              | post     |                                        |
|   |              | dosing.  |                                        |
+---+--------------+----------+----------------------------------------+
|   | **Water:**   | Water    |                                        |
|   |              | con      |                                        |
|   |              | sumption |                                        |
|   |              | not      |                                        |
|   |              | sp       |                                        |
|   |              | ecified. |                                        |
+---+--------------+----------+----------------------------------------+
|   | **E          | **Temper | > Not specified                        |
|   | nvironmental | ature:** | >                                      |
|   | c            |          | > Not specified                        |
|   | onditions:** | **Hum    | >                                      |
|   |              | idity:** | > Not specified                        |
|   |              |          | >                                      |
|   |              | **Air    | > Not specified                        |
|   |              | ch       |                                        |
|   |              | anges:** |                                        |
|   |              |          |                                        |
|   |              | **Photop |                                        |
|   |              | eriod:** |                                        |
+---+--------------+----------+----------------------------------------+
|   | *            | Vo       |                                        |
|   | *Acclimation | lunteers |                                        |
|   | period:**    | admitted |                                        |
|   |              | to       |                                        |
|   |              | clinic   |                                        |
|   |              | the      |                                        |
|   |              | a        |                                        |
|   |              | fternoon |                                        |
|   |              | before   |                                        |
|   |              | dosing   |                                        |
|   |              | the next |                                        |
|   |              | a.m.     |                                        |
+---+--------------+----------+----------------------------------------+

**B. [STUDY DESIGN and METHODS]{.underline}:**

**1. [Study dates]{.underline}:** Start: September 28, 1998, End: not
given

**2. [Volunteer population]{.underline}:** Forty volunteers were
assigned to the test groups noted in Table 1, and were admitted to the
clinic the afternoon before the study. All volunteers were healthy white
males; thirty-four were non-smokers and six were previous smokers. Four
volunteers were non-drinkers, and 36 reported the regular consumption of
approximately 1 to 20 "units" of alcohol/week (1 unit = 1 glass wine or
beer, or measure of spirit).

3.  **[Blinding:]{.underline}** The study design was double blind and
    placebo controlled, with the exception of Session 1 in which both
    volunteers received placebo. Dose escalation was not to occur if
    there were clinically significant symptoms/signs of carbamate
    toxicity or if any volunteer had 40% inhibition of RBC
    cholinesterase at a single time point or 25% inhibition at 2
    consecutive time points. If there were associated symptoms/signs of
    carbamate toxicity, no further administration of that particular
    dose would occur. The allocation of the test substance or placebo
    was randomized and based on the randomization code generated by the
    Statistics Department of Inveresk Research. A copy of the
    randomization code was held by the ICR phamacist where it was
    required for dispensing purposes and by the Regulatory Affairs
    Department at Inveresk Research. Sealed disclosure envelopes were
    also provided to ICR. In the event of an emergency requiring
    identification of the drug administered to a volunteer, the Study
    Director could request that the envelope be opened.

4.  **[Experimental Design]{.underline}:** Approximately 5 minutes after
    the completion of a "standard" breakfast, the volunteers were given
    a single dose of an oxamyl/lactose blend (Batch No. DPX-D140-196) or
    placebo in a gelatin capsule while sitting, with 150 mL water. The
    dosing schedule is presented in Table 1. Based on available animal
    data, the starting dose (0.005 mg/kg bw) was predicted to have no
    detectable effects on humans. The volunteers remained seated or
    recumbent until approximately 3 hours post-dosing, when they were
    allowed to be ambulant and have decaffeinated fluids. A light lunch
    was provided approximately 4 hours post-dosing. Volunteers were
    discharged about 24 hours post-dosing, with their agreement to
    return within 7 () days for follow-up evaluation of well-being, any
    outstanding adverse events, and for measurement of plasma and red
    blood cell (RBC) cholinesterase activity.

  ------------------- ----------- ------- ------- ------ ------ ------ -------
  **TABLE 1. Study                                                     
  design**                                                             

  **Doses                                                              
  Administered (mg/kg                                                  
  bw) and number of                                                    
  volunteers**                                                         

  Session Numbers     0 (Placebo) 0.005   0.015   0.03   0.06   0.09   0.15

  1                   2                                                

  2                   1           1                                    

  3                   1           4       1                            

  4                   1                   4       1                    

  5                   1                           4      1             

  6                   1                                  4      1      

  7                   1                                         4      

  8                   1                                                1

  9                   1                                                4

  Total Volunteers    10          5       5       5      5      5      5
  ------------------- ----------- ------- ------- ------ ------ ------ -------

Data obtained from p. 20, MRID 44912301.

5.  **[Clinical evaluation]{.underline}:** Volunteers received a
    complete screening physical examination, testing for Hepatitis B, C,
    and HIV infection, and drug-screening of urine within 14 days of
    study commencement. Blood pressure and heart rate were measured at
    screening (within 14 days prior to dosing), 16 hours pre-dose
    (admission), 30 minutes pre-dose, and 1, 2, 3, 4, 8 ,and 24 hours
    post-dose. Oral temperature was recorded at screening, 16 hours and
    30 minutes pre-dose, and 2, 4, and 24 hours post-dose. A 12-lead ECG
    was obtained at screening, 30 minutes pre-dose, and 30 minutes
    post-dose, and 1, 2, and 24 hours post-dose. Hematology and clinical
    chemistry testing was performed at screening, 30 minutes pre-dose,
    and 24 hours post-dose. Urinalysis was conducted at screening and 24
    hours post-dose. Pupillometry was performed 16 hours and 30 minutes
    pre-dose, and 1, 2, 3, 4, 8, and 24 hours post-dose using the
    optical unit (pupilscan, hand-held electronic pupillometer). Saliva
    was collected and quantified by weight 16 hours and 30 minutes
    pre-dose, and 1, 2, 3, 4, 8, and 24 hours post-dose by having the
    volunteers place 2 sterilin-treated, weighed dental rolls opposite
    the 2^nd^ molar on the upper cheek pouch on both sides for 5
    minutes. The dental rolls were then replaced in the sterilin and the
    pre- and post-collection weights were used to determine the salivary
    weight. Plasma and red blood cell cholinesterase activity were
    assayed at screening, and 2 days, 16 hours, and 30- minutes
    pre-dose, and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6,
    8, 12, and 24 hours post-dose, and at 7 ( 2) days post-dose. Plasma
    and red cell fraction (except screening and post-study samples) were
    separated and immediately snap frozen in liquid nitrogen. The
    collected plasma and red cell samples were assayed for
    cholinesterase activity according to the method of Ellman (1961)
    adapted as a clinical chemistry kit and analyzed on a Hitachi
    clinical chemistry analyzer (IR/SOP/CLC/043).

6.  **[Statistics]{.underline}:** The SAS (v6.07) statistical package
    was used to perform statistical analyses. The parameters evaluated
    included the mean, standard deviation, minimum, maximum, and number
    at each timepoint for pupillometry (initial, minimum, recovery, and
    change from initial to minimum), vital signs, saliva collection, and
    plasma and RBC cholinesterase activity. These parameters were
    analyzed and summarized by dose level and timepoint. The percentage
    change from baseline at each time point was calculated on an
    individual basis and tabulated by dose level. Baseline was defined
    as the mean of all available pre-dose values (for that individual)
    (screening, 2 days, 16 hours, or 30 minutes pre-dose).

> A repeated measures analysis of variance (ANOVA) - including terms for
> dose level, timepoint, and dose level by timepoint interaction - were
> used to analyze the percentage change from baseline in RBC and plasma
> cholinesterase activity, pupillometry, and saliva collection. At each
> timepoint, a test for linear trend with dose was performed using a
> linear contrast. Using the error variance from the ANOVA, pairwise
> comparisons between placebo and each dose level were carried out at
> each timepoint using the Student's 't'-test. If the test for linear
> trend was significant at the 5% level, then the pairwise comparisons
> at that timepoint were not adjusted for multiple comparisons. If the
> test for linear trend was not significant at the 5% level, a
> Bonferroni adjustment was applied to the pairwise comparisons at that
> timepoint (i.e., each comparison was tested at the 0.83% significance
> level). Treatment group LSMeans (i.e., means adjusted for any
> imbalance in the model) were presented together with the significance
> level of the 't' tests and the test for linear trend.
>
> Normality of distribution was examined using a Shapiro-Wilk test,
> while homogeneity of variance was assessed by plotting the residuals
> against the predicted values for the model. If there was significant
> non-normality that could not be resolved by transforming the data, the
> data were analyzed excluding outliers. If the omission of outliers had
> no effect on the conclusions, the results of the full data set only
> were reported.
>
> Descriptive statistical methods were used to summarize demographic
> data, ECG, urinalysis, and adverse events by dose level and, where
> appropriate, by timepoint. Adverse events were summarized under each
> dose level by tabulating the frequency of reports of each unique
> event, and were coded using the WHO Adverse Reaction Terminology
> (1997).

**II. RESULTS:**

**A. [CLINICAL FINDINGS]{.underline}:**

**1. [Clinical observations]{.underline}:** A total of 13 clinical
effects were reported by a total of 7 study volunteers. No clinical
signs were reported for the 0.005, 0.06 or 0.09 mg/kg dose groups. Three
placebo volunteers reported clinical signs that included bleeding gums;
secondary to trauma, headache, fever, tremor "feeling shaky", muscular
pains, and discomfort in right groin; and slightly enlarged inguinal
nodes on the right side were noted. In the 0.015 mg/kg group, clinical
signs were reported for 3 volunteers and included nausea (4 minutes) and
headache; pre-dose, and abdominal pain; 46 hours post-dose for 30
minutes. An earache was reported by one volunteer in the 0.03 mg/kg
group. Headache, sweating and epistaxis (nosebleed) were reported in the
0.15 mg/kg dose group by one volunteer. The sweating began 10 hours 50
minutes post-dose and lasted for 3 hours and 55 minutes. The nose bleed
began 22 hours and 50 minutes post-dose. All reported clinical signs in
all volunteers were gone by the post-study visit. The symptoms reported
by the volunteers typically do not correspond with the peak ChE
inhibition and fall outside the time of ChE recovery. Therefore, the
clinical observations are not considered to be treatment related.

**2. [Vital signs and ECG]{.underline}**: No dose group had changes in
vital signs or ECGs.

**3. [Cholinesterase inhibition]{.underline}:** see Tables 2 and 3.

[]{.mark}

> **Individual cholinesterase**: Four of the 5 volunteers of the high
> dose (0.15 mg/kg) group demonstrated a greater than -40% inhibition of
> plasma cholinesterase activity from that individuals baseline
> (baseline consisted of the mean of screening, -2 days, -16 hours, and
> -30 minutes pre-dosing). One of these 4 volunteers also has greater
> than -40% RBC ChE inhibition. The first volunteer had -46%, -45%, and
> -42% plasma cholinesterase activity at 60, 75, and 90 minutes
> post-dosing. The corresponding peak RBC ChE inhibition occurred at 60
> minutes (-43%). The second volunteer also displayed inhibited plasma
> cholinesterase activity at 30 (-54%), 45 (-58%), 60 (-49%), and 75
> (-39%) minutes post-dosing. Peak RBC ChE inhibition of -38% occurred
> at 45 minutes post-dosing. Plasma cholinesterase inhibition occurred
> beginning at 30 minutes (-61%) in the third volunteer until 60 minutes
> (-40%) post-dosing. A maximum of -34% RBC ChE inhibition occurred at
> 45 minutes post-dosing. Plasma cholinesterase inhibition for the
> fourth volunteer occurred at 45 minutes post-dosing only (-41%) with
> peak RBC ChE inhibition of -35% at 45 minutes post-dosing.
>
> Three of the 5 volunteers of the 0.09 mg/kg dose group exhibited a
> -20% or greater inhibition of plasma cholinesterase activity beginning
> at 45 minutes post-dosing. These 3 volunteers of the 0.09 mg/kg dose
> group exhibited -23% plasma (-7% RBC at 45 minutes), -21% plasma (-18%
> RBC at 30 minutes), and -20% plasma (-15% RBC at 120 minutes)
> cholinesterase inhibition at 45, 75, and 120 minutes post-dosing,
> respectively.
>
> **Plasma cholinesterase**: Statistical analysis of the group mean by
> time point was not performed. Instead, statistical analysis was
> performed on the percent change from baseline (average of values at
> screening, -2 days, -16 hr, and -30 min). The mean percent change in
> plasma cholinesterase activity was statistically decreased compared to
> placebo in the high dose (0.15 mg/kg) beginning at the first time
> point (-14%, 15 min) until 3 hours post-dosing (-8%), with peak
> inhibition at 45 minutes post-dosing (43%, p\<0.001). Plasma
> cholinesterase activity returned to baseline by 6 hours post-dosing.
> For the group exposed to 0.09 mg/kg, plasma cholinesterase activity
> was significantly inhibited starting at 75 minutes post-dosing (-12%
> peak, p=0.026) until 2 hours post-dosing (-10%, p=0.039) with recovery
> at 3 hours post-dosing. Maximum plasma ChE inhibition varied among
> volunteers with a maximum of -23% at 45 minutes until approximately 2
> hours
>
> (-20%) post-dosing. Within the 0.06 mg/kg dose group, the maximum
> plasma cholinesterase inhibition was -7% at 75 minutes post-dosing
> (non-statistical, p=0.22). Plasma cholinesterase activity was similar
> to placebo in the 0.005, 0.015 and 0.03 mg/kg dose groups at all time
> points. However, when the linear trend was tested for dose at each
> time point, the test was significant for every time point except at 4,
> 8, 12, and 24 hours, and 7 days post-dosing. The inclusion or
> exclusion of outlying values did not alter the results for plasma
> cholinesterase activity.
>
> **Red blood cell (RBC) cholinesterase**: As with plasma cholinesterase
> activity, RBC cholinesterase activity was analyzed as the percent
> change from baseline compared to placebo at varying time points
> post-dosing. The mean RBC cholinesterase activity of the high dose
> group (0.15 mg/kg) was inhibited significantly beginning at 30 minutes
> (-23%, p\<0.001) with peak inhibition at 45 and 60 minutes (-28% and
> -27%, respectively with p\<0.001 for both) until 2 hours post-dosing
> (-8%, p=0.011) and recovery to baseline by 3 hours post-dosing. For
> the 0.09 mg/kg dose group, the mean RBC cholinesterase activity was
> significantly decreased only at 30 minutes (-7%, p=0.016) with
> recovery following at 45 minutes post-dosing. Volunteer variation of
> RBC ChE activity at this dose at 30 minutes ranged from +8% to -18%.
> RBC cholinesterase activity was statistically similar to placebo at
> all time points in the 0.005, 0.015, 0.03, and 0.06 mg/kg dose groups.
> Analysis of a linear trend for RBC cholinesterase activity by dose at
> varying time points indicated significance from 30 minutes until 105
> minutes post-dosing.

  ------------------ ---------- ----------- ----------- ---------- ---------- ------------ ---------------
  **Table 2. Plasma                                                                        
  and RBC                                                                                  
  cholinesterase                                                                           
  activity change                                                                          
  from baseline (%)                                                                        
  over time in                                                                             
  volunteers                                                                               
  receiving oxamyl                                                                         
  (outlying values                                                                         
  included)**                                                                              

  **Time**           **Dosage                                                              
                     Group                                                                 
                     (mg/kg                                                                
                     bw)**                                                                 

                     **0**      **0.005**   **0.015**   **0.03**   **0.06**   **0.09**     **0.15**

  **Plasma                                                                                 
  cholinesterase**                                                                         
  (mean SD)                                                                                

  15 mins postdose   -1.3 6.3   -3.0 7.7    2.7 11.5    0.4 2.1    -2.4 1.7   -4.1 8.6     -14.1\*12.0

  30 mins postdose   -4.7 4.8   -4.8 6.2    0.1 8.0     2.0 1.6    -5.4 3.5   -5.6 9.1     -35.9\*\*21.9

  45 mins postdose   -7.3 7.4   -4.6 5.3    0.1 8.7     0.5 2.3    -2.1 14.7  1.2 17.7     -43.4\*\*14.7

  1 h postdose       -1.7 5.7   1.3 7.0     0.7 7.4     -1.2 4.8   -5.6 4.8   -6.2 8.4     -40.4\*\*7.2

  1 h 15 mins        -1.5 5.4   -0.4 6.9    3.6 8.2     -0.3 3.3   -7.1 4.8   -11.6\* 8.2  -35.9\*\*6.0
  postdose                                                                                 

  1 h 30 mins        -3.3 4.7   -2.6 6.4    3.4 8.1     -2.2 5.9   -4.1 4.9   -10.1 6.4    -30.2\*\*7.5
  postdose                                                                                 

  1 h 45 mins        -4.0 5.1   -1.3 6.7    3.0 10.3    -0.8 4.5   -3.9 4.2   -9.5 4.5     -25.3\*\*4.6
  postdose                                                                                 

  2 h postdose       -1.0 4.4   1.9 5.7     2.8 7.3     -2.1 2.1   -5.7 3.3   -10.2\* 6.0  -20.9\*\*4.8

  3 h postdose       0.4 5.7    3.2 5.1     6.6 5.3     5.4 2.3    -3.3 5.4   1.3 5.9      -8.0 5.8

  4 h postdose       -1.0 5.3   0.9 4.1     7.4 7.3     3.5 4.8    -1.0 4.5   1.4 3.5      -1.7 2.7

  6 h postdose       -4.4 5.0   -11.7 7.0   3.9 15.5    0.9 4.9    -4.5 3.3   -1.7 4.6     5.8 26.0

  8 h postdose       -3.7 5.3   -8.5 5.1    10.8 16.4   2.0 4.5    -2.4 4.9   0.8 4.8      2.5 24.8

  12 h postdose      -5.5 6.7   -13.0 3.7   2.6 16.2    1.8 7.3    -4.0 2.3   -2.2 5.1     1.6 16.8

  **RBC                                                                                    
  cholinesterase**                                                                         
  (mean SD)                                                                                

  15 mins postdose   4.9 10.6   2.0 7.6     -0.4 10.8   4.8 14.6   -1.3 7.2   1.0 8.9      -2.3 16.6

  30 mins postdose   7.8 11.2   11.6 4.8    1.5 8.5     5.5 10.9   -2.4 7.8   -7.3\*8.3    -23.2\*\*13.8

  45 mins postdose   6.5 10.8   -0.2 6.2    -4.8 16.0   3.0 13.8   -4.3 8.2   0.2 12.2     -27.9\*\*12.7

  1 h postdose       9.4 10.3   4.9 8.1     3.0 3.9     1.9 16.3   5.9 11.1   -0.3 7.5     -27.1\*\*10.1

  1 h 15 mins        5.5 10.3   2.5 12.4    1.0 9.9     7.3 11.3   1.6 14.0   -0.7 7.2     -16.8\*\*15.0
  postdose                                                                                 

  1 h 30 mins        11.1 8.8   3.2 9.9     2.9 6.6     6.0 11.1   4.5 9.0    1.8 6.2      -15.9\*\*9.3
  postdose                                                                                 

  1 h 45 mins        4.5 14.7   2.1 11.0    2.5 9.5     -0.1 10.5  1.9 4.1    -1.1 5.8     -9.2\*7.2
  postdose                                                                                 

  2 h postdose       7.9 9.7    0.3 2.8     -2.3 7.3    -0.5 5.4   -2.8 12.6  -2.1 7.8     -8.0 9.7

  3 h postdose       10.3 10.9  9.2 9.5     -3.7 9.5    7.8 13.4   3.2 11.6   -0.2 14.0    -0.4 6.8

  4 h postdose       12.4 10.4  8.4 11.5    9.6 8.2     -0.5 5.2   2.3 7.2    3.0 13.4     3.7 11.0

  6 h postdose       3.5 13.8   10.610.7    4.8 12.9    6.5 7.5    5.1 5.2    21.3\*14.0   10.9 6.6
  ------------------ ---------- ----------- ----------- ---------- ---------- ------------ ---------------

Data obtained from pp. 415-416, and 419-420, MRID 44912301.

\*Statistically significant at p \< 0.05, compared with controls.

\*\* Statistically significant at p 0.001, compared with controls.

mins = minutes, h = hours

+----------+----------+-------+------+------+------+------+--------+
| **Table  |          |       |      |      |      |      |        |
| 3. Mean  |          |       |      |      |      |      |        |
| values   |          |       |      |      |      |      |        |
| for      |          |       |      |      |      |      |        |
| Plasma   |          |       |      |      |      |      |        |
| and RBC  |          |       |      |      |      |      |        |
| cholin   |          |       |      |      |      |      |        |
| esterase |          |       |      |      |      |      |        |
| activity |          |       |      |      |      |      |        |
| in all   |          |       |      |      |      |      |        |
| vo       |          |       |      |      |      |      |        |
| lunteers |          |       |      |      |      |      |        |
| r        |          |       |      |      |      |      |        |
| eceiving |          |       |      |      |      |      |        |
| oxamyl** |          |       |      |      |      |      |        |
|          |          |       |      |      |      |      |        |
| **(      |          |       |      |      |      |      |        |
| outlying |          |       |      |      |      |      |        |
| values   |          |       |      |      |      |      |        |
| inc      |          |       |      |      |      |      |        |
| luded)** |          |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| **Time** | **Dosage |       |      |      |      |      |        |
|          | Group    |       |      |      |      |      |        |
|          | (mg/kg   |       |      |      |      |      |        |
|          | bw)**    |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
|          | **0**    | **0.  | *    | **0. | **0. | **0. | **     |
|          |          | 005** | *0.0 | 03** | 06** | 09** | 0.15** |
|          |          |       | 15** |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| **Plasma |          |       |      |      |      |      |        |
| cholines |          |       |      |      |      |      |        |
| terase** |          |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| s        | 5        | 53    | 5082 | 531  | 512  | 501  | 4      |
| creening | 013648.9 | 06817 | 1008 | 4842 | 5804 | 4552 | 682837 |
+----------+----------+-------+------+------+------+------+--------+
| Day -2   | 5        | 65    | 522  | 6153 | 6137 | 530  | 5      |
|          | 685671.5 | 41929 | 1784 | 1409 | 1000 | 1586 | 158935 |
+----------+----------+-------+------+------+------+------+--------+
| -16 h    | 5        | 637   | 5460 | 5664 | 578  | 514  | 4      |
|          | 473603.9 | 91017 | 1030 | 1412 | 7900 | 2412 | 945920 |
+----------+----------+-------+------+------+------+------+--------+
| -30 mins | 5        | 611   | 538  | 594  | 580  | 529  | 4      |
|          | 346593.6 | 71259 | 8844 | 3964 | 9951 | 7791 | 871777 |
+----------+----------+-------+------+------+------+------+--------+
| 15 mins  | 5        | 59    | 5455 | 5776 | 557  | 497  | 415    |
| postdose | 321767.4 | 02934 | 1367 | 1055 | 1812 | 8605 | 8\*465 |
+----------+----------+-------+------+------+------+------+--------+
| 30 mins  | 5        | 57    | 5320 | 5881 | 539  | 489  | 3140\* |
| postdose | 130639.4 | 99954 | 1175 | 1151 | 6830 | 4496 | \*1153 |
+----------+----------+-------+------+------+------+------+--------+
| 45 mins  | 4        | 582   | 5308 | 5785 | 552  | 523  | 2758\  |
| postdose | 981646.0 | 51050 | 1135 | 1091 | 7758 | 3878 | *\*739 |
+----------+----------+-------+------+------+------+------+--------+
| 1 h      | 5        | 618   | 5355 | 5677 | 538  | 485  | 2913\  |
| postdose | 287651.3 | 01088 | 1192 | 1047 | 5833 | 9448 | *\*566 |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 15   | 5        | 60    | 5484 | 5737 | 530  | 4    | 3138\  |
| mins     | 307703.7 | 51894 | 1082 | 1059 | 3843 | 574\ | *\*567 |
| postdose |          |       |      |      |      | *285 |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 30   | 5        | 59    | 5475 | 560  | 546  | 465  | 3431\  |
| mins     | 208682.6 | 19914 | 1057 | 9981 | 6818 | 8386 | *\*743 |
| postdose |          |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 45   | 5        | 601   | 5450 | 5708 | 548  | 469  | 3673\  |
| mins     | 174676.5 | 41025 | 1105 | 1082 | 0838 | 2301 | *\*705 |
| postdose |          |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 2 h      | 5        | 598   | 5440 | 5650 | 538  | 4    | 3890\  |
| postdose | 325579.8 | 81105 | 1040 | 1114 | 0796 | 667\ | *\*758 |
|          |          |       |      |      |      | *533 |        |
+----------+----------+-------+------+------+------+------+--------+
| 3 h      | 5        | 62    | 562  | 6057 | 551  | 526  | 4      |
| postdose | 402640.4 | 82971 | 8916 | 1053 | 8919 | 8602 | 513793 |
+----------+----------+-------+------+------+------+------+--------+
| 4 h      | 5        | 615   | 5680 | 5951 | 566  | 526  | 4      |
| postdose | 337725.4 | 11023 | 1063 | 1096 | 3974 | 8446 | 822787 |
+----------+----------+-------+------+------+------+------+--------+
| 6 h      | 5        | 53    | 5462 | 5793 | 546  | 511  | 51     |
| postdose | 149665.0 | 40580 | 1060 | 1016 | 2939 | 0521 | 051122 |
+----------+----------+-------+------+------+------+------+--------+
| 8 h      | 5        | 55    | 5809 | 5878 | 5591 | 524  | 4      |
| postdose | 189688.0 | 55759 | 1018 | 1190 | 1079 | 2535 | 941979 |
+----------+----------+-------+------+------+------+------+--------+
| 12 h     | 5        | 52    | 536  | 5867 | 550  | 508  | 4      |
| postdose | 080634.9 | 78663 | 1889 | 1227 | 0966 | 2503 | 938812 |
+----------+----------+-------+------+------+------+------+--------+
| 24 h     | 5        | 57    | 571  | 6276 | 5996 | 535  | 4      |
| postdose | 301744.9 | 38840 | 3840 | 1111 | 1010 | 5457 | 568484 |
+----------+----------+-------+------+------+------+------+--------+
| post     | 5        | 597   | 545  | 6038 | 583  | 529  | 5      |
| study    | 672640.8 | 81000 | 0767 | 1179 | 8722 | 2542 | 180975 |
+----------+----------+-------+------+------+------+------+--------+
| **RBC    |          |       |      |      |      |      |        |
| cholines |          |       |      |      |      |      |        |
| terase** |          |       |      |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| s        | 84331539 | 88    | 9808 | 9457 | 900  | 787  | 8      |
| creening |          | 98943 | 1242 | 1007 | 6633 | 0901 | 557585 |
+----------+----------+-------+------+------+------+------+--------+
| Day -2   | 12063928 | 1238  | 1    | 1186 | 1    | 1    | 118    |
|          |          | 01105 | 2143 | 6601 | 2194 | 1349 | 631065 |
|          |          |       | 1114 |      | 1179 | 1344 |        |
+----------+----------+-------+------+------+------+------+--------+
| -16 h    | 1        | 1283  | 1    | 1177 | 1257 | 1109 | 11     |
|          | 15011200 | 91419 | 2127 | 6991 | 0784 | 2587 | 299850 |
|          |          |       | 1023 |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| -30 mins | 11457868 | 1253  | 1171 | 1259 | 1224 | 1    | 106    |
|          |          | 41148 | 4655 | 9619 | 6699 | 1437 | 861644 |
|          |          |       |      |      |      | 2026 |        |
+----------+----------+-------+------+------+------+------+--------+
| 15 mins  | 1        | 118   | 1    | 1    | 1132 | 1    | 103    |
| postdose | 14021430 | 87890 | 1397 | 1959 | 4501 | 0512 | 461822 |
|          |          |       | 1346 | 1547 |      | 1238 |        |
+----------+----------+-------+------+------+------+------+--------+
| 30 mins  | 1        | 130   | 1    | 1    | 1119 | 9    | 8125\* |
| postdose | 16981336 | 09862 | 1645 | 2061 | 8602 | 618\ | \*1477 |
|          |          |       | 1442 | 1458 |      | *713 |        |
+----------+----------+-------+------+------+------+------+--------+
| 45 mins  | 1        | 1165  | 1    | 1    | 1    | 1    | 7605\* |
| postdose | 15511303 | 61157 | 0887 | 1766 | 1015 | 0407 | \*1043 |
|          |          |       | 1861 | 1654 | 1144 | 1249 |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h      | 1        | 1225  | 1178 | 1    | 1    | 1035 | 7695\  |
| postdose | 18781358 | 01379 | 1596 | 1642 | 2178 | 4767 | *\*874 |
|          |          |       |      | 1898 | 1286 |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 15   | 1        | 1191  | 1    | 1    | 1    | 1030 | 8753\* |
| mins     | 14581328 | 41197 | 1606 | 2298 | 1655 | 9655 | \*1079 |
| postdose |          |       | 1785 | 1816 | 1372 |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 30   | 1        | 1202  | 1176 | 1    | 1    | 1    | 8881\  |
| mins     | 20881448 | 81261 | 0571 | 2095 | 2015 | 0612 | *\*640 |
| postdose |          |       |      | 1230 | 1027 | 1244 |        |
+----------+----------+-------+------+------+------+------+--------+
| 1 h 45   | 1        | 1191  | 1    | 1    | 1171 | 1027 | 959    |
| mins     | 12861239 | 11469 | 1748 | 1418 | 9663 | 0649 | 9\*444 |
| postdose |          |       | 1426 | 1314 |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 2 h      | 1        | 119   | 1117 | 1138 | 1    | 1017 | 971    |
| postdose | 17031121 | 31981 | 0865 | 0941 | 1191 | 4909 | 3\*731 |
|          |          |       |      |      | 1699 |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 3 h      | 1        | 1275  | 1    | 1    | 1    | 1032 | 10     |
| postdose | 19461130 | 81481 | 1056 | 2309 | 1901 | 1967 | 530217 |
|          |          |       | 1580 | 1493 | 1685 |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 4 h      | 1        | 1262  | 1    | 1136 | 1175 | 1064 | 10     |
| postdose | 22111394 | 81309 | 2573 | 3747 | 7904 | 9869 | 956873 |
|          |          |       | 1528 |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 6 h      | 1        | 1291  | 1    | 1216 | 1210 | 1253 | 11     |
| postdose | 11871231 | 01618 | 1986 | 4906 | 2984 | 6436 | 723320 |
|          |          |       | 1565 |      |      |      |        |
+----------+----------+-------+------+------+------+------+--------+
| 8 h      | 1        | 110   | 1    | 1    | 1    | 1    | 11     |
| postdose | 18501876 | 47974 | 2679 | 2826 | 1050 | 1947 | 570773 |
|          |          |       | 1865 | 1170 | 1159 | 1502 |        |
+----------+----------+-------+------+------+------+------+--------+
| 12 h     | 1        | 1262  | 1    | 1    | 1176 | 1    | 12     |
| postdose | 20561323 | 81687 | 1337 | 1641 | 4753 | 2066 | 056997 |
|          |          |       | 1063 | 1152 |      | 1145 |        |
+----------+----------+-------+------+------+------+------+--------+
| 24 h     | 1        | 1171  | 1    | 1    | 1227 | 1    | 118    |
| postdose | 16391418 | 01218 | 2906 | 2131 | 5471 | 1574 | 091638 |
|          |          |       | 1605 | 1406 |      | 1002 |        |
+----------+----------+-------+------+------+------+------+--------+
| post     | 1        | 131   | 1    | 1    | 1    | 1    | 126    |
| study    | 23331887 | 20865 | 3368 | 2984 | 2775 | 2296 | 901534 |
|          |          |       | 1274 | 1386 | 1379 | 1463 |        |
+----------+----------+-------+------+------+------+------+--------+

Data obtained from pp. 419-420, and 435-447, MRID 44912301.

\*Statistically significant at p \< 0.05, compared with controls.

\*\* Statistically significant at p 0.001, compared with controls.

mins = minutes, h = hours

**4.** **[Pupillometry]{.underline}**:

> **With Outliers**: When all outlying values were included, the percent
> change of the mean initial pupil size from baseline (-30 minutes
> pre-dose) compared to placebo was decreased in the 0.06 and 0.09 mg/kg
> dose groups one hour post-dose (-14.6%, p=0.4 and -17.7% , p=0.77,
> respectively). The 0.06 mg/kg group mean initial pupil size returned
> to +2.6% of baseline by 4 hours post-dose, and the 0.09 mg/kg group
> returned to +1.9% of baseline at 8 hours post-dose. The high-dose
> group mean pupil size (initial) was reduced the most at 3 hours
> post-dose (-10.7% of baseline, p=0.42); subsequent values did not show
> a gradual increase over time. None of these reductions were
> statistically significant.
>
> **Without Outliers**: When the outlying values were included however,
> the test for distributional assumption of normality (Shapiro-Wilk
> test) was not satisfied. As a result, the pupillometry data were
> re-analyzed without outliers. Approximately 75% of the outliers were
> found in the 0.005 mg/kg dose level. When the outlying values were
> excluded, a linear trend (Bonferroni adjustment) was apparent at every
> time point.
>
> There were no significant decreases in minimum pupil size and recovery
> pupil size relative to baseline between any dose level and placebo, at
> any of the time points. Significant increases in recovery pupil size
> were observed at 2,4, 8 and 24 hour post-dosing in the 0.005 mg/kg
> group when compared to placebo.

**5. [Increased salivation]{.underline}:** Saliva weight (including
outliers) was increased in the 0.09 and 0.15 mg/kg groups (97.6%,
p=0.19; and 160.7%, p= 0.01, change from baseline at -30 minutes) at 1
hour post-dose when compared to the placebo group. A linear trend with
increasing dose was only significant (p=0.002) at the 1 hour time point;
percentage change from baseline saliva collection increased with dose.
At subsequent time points during the study, neither the mean saliva
weight nor the trend with dose were significant.

B.  **[CLINICAL CHEMISTRY]{.underline}**:

```{=html}
<!-- -->
```
1.  **[Hematology, clinical chemistry, and urinalysis]{.underline}:** No
    treatment-related effects were found at any test dose.

**III. DISCUSSION AND CONCLUSIONS:**

**A. [INVESTIGATORS' CONCLUSIONS]{.underline}:**

> The study authors concluded that the 0.005, 0.015, 0.03, and 0.06
> mg/kg dose groups had no treatment-related and biologically relevant
> inhibition in RBC or plasma cholinesterase activity, increase in
> salivary secretion, decrease in pupil size, or effect on ECGs, vital
> signs, body temperature, clinical chemistry, urinalysis, or clinical
> signs.
>
> "The 0.9 mg/kg dose group did not have any statistically significant
> increases in salivary secretion. There were no compound-related effect
> on ECGs, vital signs, body temperature, hematology, clinical
> chemistry, urinalysis, or clinical signs at any timepoint. Plasma
> cholinesterase activity was decreased at the 1 hour 15 minute (-11.6%
> from baseline), 1 hour 30 minutes (-10.1% from baseline), and 2 hours
> (-10.2 from baseline) timepoint, and RBC cholinesterase activity was
> statistically decreased at 30 minutes (-7.3%). Although these
> depressions were statistically significant, they were not considered
> to be adverse since they were relatively small in magnitude (less than
> 20%) and similar to depressions in plasma and RBC cholinesterase that
> occurred in individual volunteers within the placebo group during the
> course of the study. A statistically significant decrease in initial
> pupil size occurred at the 1 hour timepoint. This was not of clinical
> significance as minimum and recovery pupil sizes for that timepoint
> were not significantly decreased and there were no adverse effects on
> blood cholinesterase."

[]{.mark}

> "The 0.15 mg/kg dose group had no compound related effects on ECG,
> vital signs, body temperature, hematology, clinical chemistry,
> urinalysis or clinical signs at any timepoint. At the 1-hour
> assessment, there was a statistically significant decrease in initial
> pupil size and a statistically significant increase in saliva
> collected. In addition, statistically significant depressions in
> plasma cholinesterase activity were present at all time points up to
> and including 3 hours post-dosing and statistically significant
> depressions in RBC cholinesterase activity was observed from 30
> minutes up to and including 1 hour 45 minutes. The period of maximum
> depression occurred at 45 and 60 minutes for plasma cholinesterase and
> from 30 to 60 minutes for RBC cholinesterase. Plasma and RBC
> cholinesterase activities returned to baseline within 4 and 3 hours
> following administration of the test substance, respectively."

**B. [EPA CONCLUSIONS]{.underline}:**

> No dose group had changes in respiratory rate, ECGs, vital signs,
> hematology, clinical chemistry, urinalysis, or clinical signs. There
> were no significant decreases in minimum and recovery pupil sizes in
> any dose group compared to placebo. Plasma and RBC cholinesterase
> activity typically returned to normal by 3 hours post-dosing in all
> groups. In the high dose (0.15 mg/kg) plasma and RBC cholinesterase
> activity both peaked (43% and 28%, respectively) at 45 minutes
> post-dosing with recovery by 3 to 4 hours post-dosing. Plasma
> cholinesterase inhibition peaked at 75 minutes (-12%) and recovered by
> 3 hours post-dosing in the 0.09 mg/kg dose group. RBC cholinesterase
> inhibition was statistically decreased (-7%) at 30 minutes only. No
> differences in plasma or RBC cholinesterase activities were observed
> in the other dose groups compared to control.
>
> Under the conditions of this ascending oral dose study in humans, 0.09
> mg/kg/day represents a level where 7-12% plasma and RBC ChE inhibition
> was observed. Three of 5 volunteers at this dose (0.09 mg/kg/day)
> exhibited greater than 20% plasma ChE inhibition. Therefore, 0.06
> mg/kg/day is considered the NOAEL.
>
> Additionally, the Agency used the RBC ChE inhibition time-course data
> for input into the Agency's BMDS model. The BMD~10~ is 0.083 mg/kg and
> BMDL~10~ of 0.069 mg/kg. The BMD and BMDL were considered for the NMC
> carbamate cumulative risk assessment for refinement of the
> interspecies extrapolation factor for oxamyl.

**C. [DEFICIENCIES]{.underline}:**

> There were no study deficiencies identified that would have affected
> the outcome and conclusions of this study.