Page 2 of 13 

1. Overview 

Oxamyl is a member of the N-Methyl Carbamate (NMC) common mechanism group and 

was therefore included in the NMC Cumulative Risk Assessment (CRA). NMCs share 

the ability to inhibit the acetyl cholinesterase enzyme (AChE) via carbamylation. Due to 

the rapid nature of NMC toxicity, the acute inhibition of AChE therefore, is the main 

exposure duration of concern. 

This memo will first highlight the changes in the database for oxamyl since the 1999 

Reregistration Eligibility Decision (RED). These changes are followed by the results of 

the comparative cholinesterase study and the human RBC AChE study. A side-by-side 

comparison of all available AChE data for the point of departure is then presented 

followed by the updated FQPA factor. The memo further outlines the differences in the 

2009 dose-response assessment (acute dietary, dermal, and inhalation) compared to the 

1999 RED. 

2. Cholinesterase Data since 1999 

The Agency completed the Reregistration Eligibility Decision (RED) for oxamyl in 1999 

based on the available toxicological information at the time. Since the published oxamyl 

RED in 1999, additional toxicological information concerning carbamates was submitted, 

in part, to support the NMC CRA. 

The following table summarizes the acute toxicity studies available since the 1999 RED. 

In addition, a human study was evaluated by the Human Studies Review Board (April, 

2006) and was determined to be both ethically and scientifically valid for use in risk 

assessment (http://www.epa.gov/osa/hsrb/apr-4-6-2006-public-meeting.html). The list of 

new oxamyl studies with appropriate AChE data are listed below. 

Table 1. New studies available since the time of the 1999 oxamyl RED 

Study MRID Route AChE Data

Comparative Cholinesterase Assay Study (CCA) 46615301 oral brain, RBC 

Reversibility Oxamyl Study 44472001 oral brain, RBC 

Human RBC AChE Oxamyl Study 44912301 oral RBC 

NHEERL NA oral brain, RBC 

Acute Inhalation Study 45155801 inhalation brain,RBC 

3. Oral Cholinesterase Data 

a. Comparative Cholinesterase Study 

As noted in Table 2, a comparative cholinesterase study is available in which 

cholinesterase activity was measured in both postnatal day 11 (PND 11) pups and adult 

rats (46615301). Similar to results in comparative cholinesterase studies with other Nmethyl carbamates, the oxamyl comparative cholinesterase study revealed that PND11 

pups are more sensitive to oxamyl than adult rats. The recovery half-life estimate is also 

greater in PND11 pups than adults, indicating a longer AChE recovery time in pups than 

adults. 
Page 3 of 13 

EPA performed a benchmark dose (BMD) analysis in 2008 using the same methodology 

used in the NMC cumulative risk assessment. Modeling suggestions by Exponent 

(MRID 47386001) were also considered in the 2009 BMD analysis. For further details 

concerning the 2009 BMD analysis please refer to the 2009 BMD memo (Reaves 2009, 

TXR# 0055282). The results of the 2009 BMD10 and BMDL10 estimates for both pups 

and adults are listed below (Table 2). A ratio of adult to juvenile BMD10 estimates for 

brain and RBC ChE are also provided for use in the updated data-derived FQPA factor. 

Table 2. Updated Comparative Cholinesterase Study Results (MRID 46615301, 

BMD report September 30, 2009) 

 Brain (mg/kg) RBC (mg/kg) 

Age BMD10 BMDL10 BMD10 BMDL10 

Adults 0.177 0.145 0.079 0.052 

PND11 pups 0.067 0.043 0.059 0.039 

FQPA* 2.640 1.338 

Recovery 1⁄2 Life: Confidence Interval

PND11 Recovery half-life (95% CI): Brain 1.34 hours (0.473, 3.788 hrs) 

 RBC 2.54 hours (1.043, 6.201 hrs) 

*The FQPA factor is based solely on the ratio of BMD10 adult to juvenile rats from the CCA study. 

The CCA study demonstrates that juvenile (PND11) rats are more sensitive (i.e., lower 

BMD10 and BMDL10) to oxamyl than adult rats. A comparison of BMD10s for brain 

(0.067 mg/kg) and RBC (0.059 mg/kg) demonstrate little difference in compartment 

sensitivity in the young (1.14x). Examination of the range between the BMD10 and 

BMDL10 in PND11 rats for both brain (0.067/0.043=1.6x) and RBC (0.059/0.039=1.5x) 

also suggest less than a 2-fold difference. For the adults, however, the RBC AChE data 

are especially low in this study compared to other adult RBC data (Table 3). 

Specifically, the adult RBC BMD10 is 0.079 mg/kg and BMDL10 is 0.052 mg/kg. This 

suggests that RBC AChE inhibition is more sensitive in adult rats than the brain for 

oxamyl. The difference in BMD10 and BMDL10 for both adult brain (0.177/0.145=1.2x) 

and adult RBC (0.079/0.052=1.5x) is less than 2-fold as in the PND11 pups. This lower 

adult RBC BMD10 estimate influences the FQPA factor for RBC. Specifically, this lower 

adult RBC BMD10 reduces the difference between adults and PND11 pups (0.079/0.059 

= 1.338x).

The CCA study also demonstrates that the recovery half-life is slightly longer in the 

PND11 pups than in adults. The confidence interval for the RBC half-life is wider than 

that of the brain, likely to variability in the data. 

b. Combined Adult BMD Results for Oxamyl 

As part of the comment period for the NMC CRA in 2007, an error concerning a controlonly study for oxamyl was identified (MRID 44420301). This control-only study 

reported AChE data for the acute neurotoxicity study (MRID 44254401). The data from 

the acute neurotoxicity study was inadvertently entered into the BMD files instead of the 

control data. Therefore, some of the ChE data from the acute neurotoxicity study was 
Page 4 of 13 

entered twice. HED has corrected the control only data in the BMD files for oxamyl. A 

BMD analysis in June 2008 reflected the input control-only error as well as the additional 

AChE data since the time of the 1999 RED. A September 2009 BMD analysis was 

performed based on modeling suggestions by Exponent and submitted by DuPont (MRID 

47386001). For details surrounding the Exponent modeling suggestions please refer to 

the 2009 Response Memo (TXR# 0055219). Table 3 presents the updated BMD results 

for the combined AChE data from all of the appropriate oxamyl studies. 

Table 3. Combined BMD results for brain and RBC AChE data in adult rats (study 

MRIDs: 44254401, 44472001, 46615301, NHEERL, BMD analysis of September 30, 

2009) 

 BMD10 BMDL10 

Brain (mg/kg) 0.184 0.155 

RBC (mg/kg) 0.154 0.090 

Recovery 1⁄2 Life: Confidence Interval

Adult Recovery Half-Life (95% CI): Brain 0.616 hours (0.547, 0.692 hrs) 

 RBC 0.758 hours (0.650, 0.884 hrs) 

 

The combined adult AChE data for oxamyl suggest that the BMD10s for brain and RBC 

are similar. However, the BMDL10 for RBC (0.090 mg/kg) is lower than the brain 

BMDL10 (0.155 mg/kg), likely due to variability in the RBC data. A comparison of the 

CCA data for adult brain BMD10 (0.177 mg/kg) and BMDL10 (0.144 mg/kg) is also very 

similar to the combined adult brain BMD10 (0.184 mg/kg) and BMDL10 (0.155 mg/kg). 

A similar comparison of the adult RBC data from only the CCA data to the combined 

adult data demonstrates that the RBC data from only the CCA study is 2-fold lower than 

the combined RBC data (0.154 mg/kg combined adult RBC/0.079 mg/kg CCA only adult 

RBC=1.9x). Furthermore, the CCA only adult RBC BMDL10 is 1.7-fold lower (0.09 

mg/kg combined RBC/0.052 mg/kg CCA only adult RBC=1.7x) than the combined adult 

RBC data. Therefore, the FQPA factor derived from the ratio of BMD10 of adult/PND11 

pups may be artificially low based on the lower adult BMD10 estimate from the CCA 

study. 

The combined adult data also demonstrate similar recovery half-life times and tight 

confidence intervals for brain and RBC. The adult RBC and brain half-life estimates are 

slightly shorter (≈ 1 hour) than the PND11 half-life estimates (1.5 to 2.5 hours). 

c. Human Oral Study 

The oxamyl human toxicity study was performed in 40 male subjects (19-39 years) in a 

dose-escalation fashion that provided dose-response data for RBC AChE. AChE activity 

was measured every 15 minutes for the first two hours post-dosing, then hourly through 8 

hours, at 24 hours, and one week later. The multiple sampling over time showed the 

progression of inhibition of AChE activity until peak inhibition and then demonstrated 

enzyme recovery. For obvious reasons, only RBC AChE data are available from the 

human study. 
Page 5 of 13 

Table 4. Oxamyl Human Study Results (MRID 44912301, BMD report June 8, 2005)

 

 BMD10 BMDL10 Ratio (BMD10 rat/human (Interspecies))

Human RBC 0.083 0.069 0.154/0.083=1.86 

(mg/kg) 

 Recovery 1⁄2 Life: Confidence Interval

Human Recovery Half-Life (95%): 2.37 hours (1.45, 3.85 hrs) 

The AChE data from the human study demonstrate less than a 1.5-fold difference 

between the RBC BMD10 and BMDL10 (0.083 mg/kg/0.069 mg/kg= 1.2x). The human 

adult recovery half-life estimate (2.37 hours) is similar to that of the juvenile RBC halflife estimate (2.54 hours). The confidence interval of the adult human half-life is also 

well within the confidence interval of the PND11 RBC half-life. The interspecies factor 

is based on the ratio of BMD10s for the adult combined RBC rat to adult RBC human 

(0.154 mg/kg/0.083 mg/kg = 1.86x). 

4. Point of Departure Options for Oxamyl aPAD 

Since there are multiple studies for oxamyl with appropriate AChE data for both brain 

and RBC, there are several options for using the AChE data in the single chemical risk 

assessment. A comparison of the AChE data and appropriate uncertainty factors for the 

single chemical risk assessment as well as that used in the Revised NMC CRA (9/24/07) 

are listed in Table 5. It should be noted that the revised NMC CRA was based on the 

oxamyl brain BMDL10 in adult rats at the time (0.18 mg/kg). This older BMD analysis 

was based on an indentified data entry error in which the acute neurotoxicity study data 

was inadvertently entered as control-only data. Therefore, the BMD, FQPA factor, and 

interspecies factor for the NMC CRA were all based on this older analysis. 

Table 5. Revised Point of departure (PoD) Comparison for Oxamyl 

Endpoint 1. Pup 

Brain 

2. Pup 

RBC 

3. Adult 

Brain 

4. Adult 

RBC 

5. Human 

RBC 

6. Human 

RBC 

NMC 

CRA3

PoD (mg/kg) BMDL10

0.043 

BMDL10

0.039 

BMDL10

0.155 

BMDL10

0.090 

BMDL10

0.069 

BMDL10

0.069 

BMDL10

0.18 

FQPA factor1 None None 

Brain 

FQPA 

2.64x 

RBC 

FQPA 

1.34x 

RBC 

FQPA 

1.34x 

Brain 

FQPA 

2.64x 

FQPA 

3.48x 

Intra-species 

factor 10x intra 10x intra 10x intra 10x intra 10x intra 10x intra 10x intra 

Inter-species 

factor2 1.86x inter 1.86x inter 1.86x inter 1.86x inter None None 3x inter 

aRfD/aPAD 0.0023 0.0021 0.0031 0.0036 0.0051 0.0026 0.0017 

1

 FQPA based on ratio of BMD10 adult/BMD10 pup from CCA study. 2

 Interspecies factor based on ratio of BMD10 rat/ BMD10 human. 3 Revised NMC CRA (9/24/07) based on adult rat brain BMDL10 from a 2006 analysis which did not 

incorporate the errors from the control only study. The resulting interspecies factor was 3x. 
Page 6 of 13 

Looking across the 6 options for the single chemical risk assessment as listed in Table 5, 

the difference in options for the aPAD is 2.4 fold (0.0051 mg/kg/0.0021 mg/kg = 2.4x). 

This 2.4x difference is slightly greater than the options considered for methomyl (most 

options approximately 1.6x) and aldicarb (1.5x or less) which also had human RBC 

AChE data. However, the most consistent aPAD across the 6 options is approximately 

0.002 mg/kg (options 1, 2, 3, and 6 from Table 5). In fact, use of the brain FQPA factor 

with the human RBC data also suggests an aPAD of 0.0026 mg/kg. Since brain data will 

never be available in humans, the brain FQPA from the rodent data would be protective 

of the brain compartment in humans. Option 5 with an aPAD of 0.0051 mg/kg is higher 

than the other aPAD options since the RBC FQPA of 1.34x is likely influenced by the 

rather low adult RBC BMD10 estimate from the CCA study. This resulted in the 

artificially higher aPAD of 0.0051 mg/kg which is not consistent with the other aPAD 

options. The NMC CRA also relied on an aPAD (0.0017 mg/kg) that was essentially 

0.002 mg/kg. Therefore, based on this weight of the evidence approach to all the data 

available for oxamyl, the most appropriate aPAD is 0.0026 mg/kg based on the human 

RBC BMDL10 of 0.069 mg/kg, brain FQPA factor of 2.64 x, and 10x intraspecies factor. 

This aPAD is supported by the other 3 options either using the juvenile or adult AChE 

data as the PoD. 

The 2.5 hour half-life estimate from the human study is also similar to the central 

estimates from the CCA study (1.3 hr brain, 2.5 RBC) and therefore appropriate for use 

in risk assessment. 

5. FQPA Considerations 

a. 1999 Risk Assessment: 

After consideration by the FQPA Safety Factor Committee (July 15, 1999), the FQPA 

safety factor was reduced to 1x based on (taken from pg 12 of 1999 HED chapter): 

b. Updated FQPA: 

Since the time of the 1999 RED, the comparative cholinesterase study in which the 

sensitivity of the young to NMC’s is best evaluated has become available. Similar to 

results in comparative cholinesterase studies with other N-methyl carbamates, this 

comparative cholinesterase study revealed that PND11 pups are more sensitive to oxamyl 
Page 7 of 13 

than adult rats. The FQPA factor is based on the ratio of the adult BMD10 to PND11 

BMD10. Cholinesterase data from this one comparative cholinesterase study indicates that 

the PND11 pups were 2.64 fold more sensitive than adult rats to brain cholinesterase 

inhibition. The FQPA factor is not appropriate for pregnant females since the 

developmental studies did not indicate susceptibility. Therefore, for the single chemical 

risk assessment for oxamyl, the FQPA factor may be applied to the oral, dermal, and 

inhalation assessments for those scenarios involving children. 

6. Oxamyl Dose-Response Assessment 

a. Acute Dietary

i. 1999 Acute Dietary 

The 1999 RED established an acute dietary point of departure (PoD) for the general 

population based on the acute neurotoxicity rat study (MRID 44254401, 44420301, 

44740701). The LOAEL of 0.75 mg/kg/day for females, and 1.0 mg/kg for males, based 

on clinical signs, FOB effects, decreased plasma, RBC, and brain AChE activity. The 

NOAEL was 0.1 mg/kg/day. An uncertainty factor of 10x was applied for intraspecies 

variability and 10x for interspecies extrapolation. After consideration by the FQPA 

Safety Factor Committee (July 15, 1999), the FQPA safety factor was reduced to 1x. 

The aPaD was determined to be 0.001 mg/kg 

ii. 2009 Acute Dietary 

The updated acute oral point of departure (PoD) for the general population is based on 

the weight of the evidence of available AChE data (rodent and human) for oxamyl. 

Therefore, the BMDL10 of 0.069 mg/kg, based on RBC AChE inhibition from a human 

study with males (MRID 44912301), is appropriate for use as the PoD. To account for 

sensitivity in the young, a 2.64x FQPA factor is appropriate based on the ratio of adult 

brain BMD10 to the PND11 brain BMD10 both from the CCA study (i.e., 0.177/0.067= 

2.640x). The inter-species factor is not appropriate since the PoD is based on human 

RBC AChE data. The intra-species factor remains 10x. The final aPAD is 0.0026 mg/kg 

and is appropriate for infants/children. The FQPA factor may be removed for scenarios 

with adults. The half-life estimate of 2.5 hours from the RBC AChE data in PND11 pups 

is appropriate for both children and adults. 

b. Dermal

i. 1999 Dermal PoD 

A 21-day dermal toxicity study in rabbit (MRID 44751201) was used for both the shortterm and intermediate-term dermal scenarios. Another rabbit dermal study (40827601) 

was available but not relied upon for risk assessment. The NOAEL of 50 mg/kg 

established the PoD in the 1999 RED. The LOAEL of 75 mg/kg/day was based on 

decreases in plasma, RBC, and brain cholinesterase in females. The MOE was 100. 
Page 8 of 13 

ii. 2010 Dermal PoD

Since the 1999 RED, a BMD analysis that combined the AChE data from the same 4-

week dermal adult rabbit study used in the 1999 RED as well as an older rabbit dermal 

study (40827601; available at the time of 1999 RED) was performed as part of the NMC 

CRA. However, a recent submission (1-15-2010, MRID 47958101) indicated significant 

differences in dose-response between the two dermal studies. This submission suggested 

that a statistical evaluation of the ChE data from both studies should not be performed for 

BMD modeling. As part of the Agency review of this submission, HED considered the 

study protocols and ChE results from both dermal studies (D373514, TXR 0055348). As 

a result of this review, the newer 21-day dermal study (MRID 44751201) was considered 

unacceptable/non-guideline due to critical flaws in the study (D376935, TXR 0055349). 

Therefore, the newer 21-day dermal study could not be used as part of BMD modeling 

for use in risk assessment. A new BMD analysis (D376936) was performed based on the 

single acceptable/guideline 21-day dermal toxicity study in rabbits (MRID 40827601). 

A BMD is preferred over a NOAEL and LOAEL approach since it provides the 10% 

inhibition level based on AChE data from multiple studies and eliminates the problem of 

dose spacing. Therefore, the BMD analysis provides the central estimate (BMD10) and 

lower limit (BMDL10) for both RBC and brain AChE data (D376936, TXR0055350, 

April 29, 2010). The power of the BMD analysis allows for the refinement of the true 

NOAEL based on dose-response. 

Table 6. Dermal BMD results for oxamyl (mg/kg)

 BMD10 BMDL10 

Brain 20.21 15.89 

RBC 23.08 7.99

 

Comparison of the BMD10 to BMDL10 for both RBC and brain suggest that RBC ChE is 

slightly more variable (23.08/7.99=2.88x) than brain (20.21/15.89=1.27x) (Table 6). The 

BMD10s for RBC and brain, however, are similar (1.14x). 

The revised dermal BMD analysis results in a dermal point of departure of 8.0 mg/kg 

based on RBC ChE inhibition. Based on this revision, dermal risks may now be 

aggregated with inhalation risks (inhalation points of departure are 0.13 mg/kg for nonoccupational and 0.39 mg/kg for occupational) since both endpoints are based on RBC 

ChE inhibition. However, the MOEs for the dermal and inhalation routes are not the 

same since the RfC methodology for inhalation results in an MOE of 30 and not 100 as is 

used for dermal. The Aggregate Risk Index (ARI) is the preferred aggregate approach 

when the uncertainty factors differ by routes of exposure (USEPA, 1998).

Due to the rapid recovery of cholinesterase inhibition, only a single day assessment is 

necessary. 
Page 9 of 13 

c. Inhalation

i. 1999 Inhalation PoD 

For the inhalation scenarios in the 1999 RED, the acute oral neurotoxicity rat study was 

used as the inhalation PoD for both the short- and intermediate-term scenarios. The 

NOAEL of 0.1 mg/kg and LOAEL of 0.75 mg/kg were based on clinical signs, and 

decreased plasma, RBC, and brain AChE inhibition in females. The chronic dog study 

was relied on for the PoD of the long-term inhalation scenario. The MOE was 100 and 

100% inhalation absorption was assumed. 

ii. 2009 Inhalation PoD 

Since the 1999 RED an acute (single day, 4 hours) inhalation toxicology study (MRID 

45155801) is available for oxamyl which was also used in the NMC CRA. Since 

inhalation specific data is available for oxamyl, the RfC methodology is appropriate for 

extrapolating rats to humans. The RfC methodology and its application here is discussed 

more below. Furthermore, since an aerosol and not a vapor was generated in this 

inhalation study, the RfC methodology can account (regional deposited dose ratio or 

RDDR) for this particle exposure. Based on the particle dimensions described in the 

inhalation study (i.e., MMAD=0.85; Sigma σ = 2.30), the RDDR value is 2.5 for this 

assessment. Brain and RBC AChE inhibition were measured at the end of the study at an 

appropriate acute time-point. The BMD analysis indicates a robust dose-response 

relationship for assessing AChE activity with RBC and brain. The inhalation BMD 

results are given below in Table 7 (Setzer RBC oxamyl, 6/24/05; Setzer brain oxamyl, 

6/9/05). The BMD analysis suggests that the RBC compartment is approximately 2.5-

fold (0.004/0.002=2.5x) more sensitive than the brain compartment. This is opposite of 

the dermal data in which brain was more sensitive (2x-3.3x). 

Table 7. Inhalation BMD results for oxamyl

 BMD BMDL10 (mg/L) 

Brain 0.005 0.004

RBC 0.002 0.0018

The NMC CRA relied on brain data and therefore the BMD10 and BMDL10 for the brain 

compartment. However, for the single chemical assessment consideration is given for the 

variability in the data as well as sensitivity between compartments. Comparison of the 

BMD and BMDL estimates for both brain (0.005/0.004=1.25x) and RBC (0.002/0.0018-

1.1x) suggest little variability in the data. Since RBC are 2-fold more sensitive than brain 

and this sensitivity is not due to variability in the data, then the RBC BMDL10 of 0.0018 

mg/L is appropriate as the PoD for the inhalation route of exposure. This BMDL10 results 

in 1.8 mg/m3 which are appropriate for use in the RfC methodology which is explained 

further below. 

Human data are not available for the oxamyl inhalation risk assessment. Therefore, the 

methods and dosimetry equations described in EPA’s reference concentration (RfC) 

guidance (1994) are suited for calculating human equivalent concentrations (HECs) and 

for use in margin of exposure (MOE) calculations. Compared to the methods previously 
Page 10 of 13 

used by OPP, the dosimetry equations in the RfC guidance more appropriately address 

different properties of gases and particles, different properties of reactive and nonreactive compounds, and explicitly consider some differences in the structure of the 

respiratory tract between laboratory animals and humans. As performed by HED for 

other chemicals, OPP has used the dosimetry equations from the RfC guidance to develop 

HECs to estimate acute, short-, and intermediate-term inhalation risk to oxamyl. 

In the RfC methodology, different HECs may be calculated for the same experimental 

NOAEL due to: 

1. Different algorithms are used to derive HECs for systemic versus port-ofentry effects. Therefore, HECs are calculated separately for systemic versus

port-of-entry effects. Systemic HECs are dependent upon the regional gas 

dose ratio (RGDR). Calculations used to estimate the inhalation risk to 

humans from aerosols are dependent not on the RGDR as for gases, but on the 

regional deposited dose ratio (RDDR). The RDDR is a multiplicative factor 

used to adjust an observed inhalation particulate exposure concentration of an 

animal to the predicted inhalation particulate exposure concentration for a 

human. 

2. Time adjustments are needed for nonoccupational versus occupational 

exposure scenarios. HECs for non-occupational exposure are based on the 

numbers of hours an individual may be at home. Therefore, the most 

conservative estimate of hours spent at home would be 24 hours/day and 7 

days/week. In comparison, the average work week for an occupational 

worker is 8 hours/day and 5 days/week. 

Table 8: HEC Array for Acute Non-Occupational Risk Assessment 

Relevant Study 

BMD10 or 

LOAEL 

(mg/L) 

BMDL10 or 

NOAEL 

(mg/L) 

Da Dh Wa Wh RDDR HEC 

(mg/m3) inter intra UF

Acute Inhalation Exposure

4 hr inhalation - Rat 

(46903529) 

SystemicRBC AChE 0.002 0.0018 

(1.8 mg/m3

) 4 24 1 1 2.5 0.75 3 10 

Table 9: HEC Array for Acute Occupational Risk Assessment 

Relevant Study 

BMD10 or 

LOAEL 

(mg/L) 

BMDL10 or 

NOAEL 

(mg/L) 

Da Dh Wa Wh RDDR HEC 

(mg/m3) inter intra UF

Acute Inhalation Exposure

4 hr inhalation - Rat 

(46903529) 

SystemicRBC AChE 0.002 0.0018 

(1.8 mg/m3

) 4 8 1 1 2.5 2.25 3 10 
Page 11 of 13 

Key for Array Table

LOAEL: Lowest observed adverse effect level 

Da: Daily animal exposure (hrs/day) 

Wa: Weekly animal exposure (days/week) 

RGDR: Regional Gas Dose Ratio 

inter: interspecies extrapolation uncertainty factor 

Dh: Anticipated daily human exposure (hrs/day) 

Wh: Anticipated weekly human exposure (days/week) 

HC: Human Concentration

HEC: Human Equivalent Concentration 

intra: intraspecies variation uncertainty factor 

UF: Other uncertainty factor(s) 

Conversion of inhalation exposure (mg/L) to oral equivalent doses (mg/kg) 

Equation 4 of the HED Policy Memo on Route-to-Route Extrapolations (Stasikowski 

Memo, 10-10-1998) was used to convert the oxamyl inhalation HEC to an oral equivalent 

dose. Equation 4 of the policy memo is outlined below: 

Equation 4 mg/L x A x RV x D x AF = mg/kg 

 BW 

Definitions (definitions take from page 8 of the HED policy memo) 

A Absorption- The ratio of deposition and absorption in the respiratory tract compared to absorption 

by the oral route. Since inhalation and oral absorption data are rarely available, a default A of 1 is 

commonly used. 

AF Activity Factor- Animal default is 1; human AFs are tabulated in Table 3. 

BW Body Weight- Mean animal or human body weight in kg (defaults in Table 2). 

D Duration- Duration of daily animal or human exposure (hours). 

RV Respiratory Volume- Mean liters of air respired per hour while at rest (default values are in Table 

2). 

Therefore, using Equation 4: the oral equivalent dose is 0.13 mg/kg nonoccupational and 0.39 mg/kg occupational. 

 RBC Non-Occupational: 

0.00075 mg/L x 1 x 10.26 (M & F Sprague Dawley rats) x 4 hrs x 1= 0.13 mg/kg 

 0.236 kg (both sexes) 

RBC Occupational: 

0.00225 mg/L x 1 x 10.26 (M & F Sprague Dawley rats) x 4 hrs x 1=0.39 mg/kg 

 0.236 kg (both sexes)

When conducting inhalation risk assessments, the magnitude of the UFs applied is 

dependent on the methodology used to calculate risk. For studies in this risk assessment 

with inhalation animal data, UFs are based on the RfC methodology developed by the 

Office of Research and Development (ORD) for the derivation of inhalation reference 

concentrations (RfCs) and human equivalent concentrations (HECs) for use in margin of 

exposure (MOE) calculations. Since the RfC methodology takes into consideration the 

pharmacokinetic (PK) differences but not the pharmacodynamic (PD) differences, the UF 

for interspecies extrapolation may be reduced to 3X (to account for the PD differences) 

while the UF for intra-species variation is retained at 10X1

. Thus, the UF when using the 

RfC methodology is customarily 30X. The MOE of 30 is appropriate for adults, not 

 

1

 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans 

which are not accounted for in the RfC methodology. 
Page 12 of 13 

infants/children. There are no data to refine the intra- and inter-species factors for the 

dermal route of exposure. 

As stated previously, due to the rapid recovery of cholinesterase inhibition only a single 

day assessment is necessary. 

A common toxicological endpoint now exists for the dermal and inhalation routes, RBC 

ChE inhibition. The revised dermal BMD analysis results in a dermal point of departure 

of 8.0 mg/kg based on RBC ChE inhibition. Based on this revision, dermal risks may 

now be aggregated with inhalation risks (inhalation points of departure are 0.13 mg/kg 

for non-occupational and 0.39 mg/kg for occupational) since both endpoints are now 

based on RBC ChE inhibition. However, the MOEs for the dermal and inhalation routes 

are not the same since the RfC methodology for inhalation results in an MOE of 30 and 

not 100 as is used for dermal. The Aggregate Risk Index (ARI) is the preferred aggregate 

approach when the uncertainty factors differ by routes of exposure (USEPA, 1998).
Page 13 of 13 

7. 2010 Endpoint Table for Oxamyl 

Table 10. Summary of Toxicological Dose and Endpoints for Oxamyl for Use in Human Health Risk 

 Assessment1

Exposure 

Scenario 

Point of Departure 

(mg/kg/day) 

Uncertainty/FQ

PA Safety 

Factors 

RfD, PAD, LOC 

for Risk 

Assessment 

Study and Toxicological 

Effects 

Acute Dietary 

All 

populations 

0.069 mg/kg 

UFA=1x 

UFH=10x 

FQPA SF=2.64x 

(brain) 

aRfD=0.0069 

aPAD= 0.0026 

(1⁄2 -life 2.5 hours) 

Human Study (MRID 

44912301) 

BMD10= 0.083 mg/kg 

BMDL10= 0.069 mg/kg, based 

on RBC AChE inhibition 

Chronic 

Dietary 

Due to the rapid recovery of ChE activity, acute exposure from oxamyl is the main duration of 

concern. 

Incidental Oral 

(All durations) Based on the current oxamyl uses, an incidental oral endpoint is not required. 

Dermal 8.0 mg/kg 

 (RBC ChE) 

UFA=10x 

UFH=10x 

FQPA SF=1x 

MOE = 100 

(adult) 

21-day dermal rabbit study 

(40827601) 

RBC BMD10 is 23.1 mg/kg 

RBC BMDL10 is 8.0 mg/kg 

Dermal 

Long-Term 

(>6 mos) 

Due to the rapid recovery of ChE activity, the acute exposure from oxamyl is the main duration of 

concern. 

Inhalation 

RBC Occupational: 

HEC = 2.25 mg/m3 or 

0.39 mg/kg 

RBC Non-Occupational: 

HEC= 0.75 mg/m3 or 

0.13 mg/kg 

UFA=3x 

UFH=10x 

FQPA SF= 1x 

MOE = 30 (adult) 

Acute inhalation rat 

(45155801) 

RBC BMD10= 0.002 mg/L 

RBC BMDL10= 0.0018 mg/L, 

based on RBC AChE 

inhibition in both sexes. 

Inhalation 

Long-Term 

(>6 mos) 

Due to the rapid recovery of ChE activity, the acute exposure from oxamyl is the main duration of 

concern and a long-term assessment is not appropriate for oxamyl. 

Cancer (oral, 

dermal, 

inhalation) 

Determined to be “not likely” a human carcinogen (Memorandum: HIARC report, Geruva Reddy, 

8/31/1999) 

1 Explanation of Abbreviations: UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). 

UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA 

Safety Factor. aPAD = population adjusted dose. RfD = reference dose. MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. HEC = Human Equivalent Concentration. RDDR = regional deposited dose ratio.