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 Cumulativ e Risk Assessment (CRA). NMCs share the ability to inhibit the acet yl cholinesterase enzyme (ACh E) 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 change s 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, de rmal, 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 informati on at the time. Since the published oxamyl RED in 1999, additional toxicological inform ation concerning carbamates was submitted, in part, to support the NMC CRA.

The following table summarizes the acute toxi city studies availabl e 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 va lid 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 sin ce 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 cho linesterase study is available in which cholinesterase activity was measured in bot h postnatal day 11 (PND 11) pups and adult rats (46615301). Similar to re sults in comparativ e cholinesterase st udies with other N

methyl carbamates, the oxamyl comparative cholinesterase study revealed that PND11 pups are more sensitive to oxamyl than adult ra ts. 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 assessm ent. Modeling suggestions by Exponent (MRID 47386001) were also considered in the 2009 BMD analysis. For further details concerning the 2009 BMD analysis please re fer to the 2009 BMD memo (Reaves 2009, TXR# 0055282). The results of the 2009 BMD 10 and BMDL 10 estimates for both pups and adults are listed below (Table 2). A ratio of adult to juvenile BMD 10 estimates for brain and RBC ChE are also provided for us e in the updated data-d erived FQPA factor.

Table 2. Updated Comparative Cholinesterase Study Results (MRID 46615301, BMD report September 30, 2009) Brain (mg/kg) RBC (mg/kg) Age BMD 10 BMDL 10 BMD 10 BMDL 10 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% C I): 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 BMD 10 adult to juvenile rats from the CCA study.

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

BMD 10 and BMDL 10 ) to oxamyl than adult rats. A comparison of BMD 10 s for brain (0.067 mg/kg) and RBC (0.059 mg/kg) demonstr ate little difference in compartment sensitivity in the young (1.14x). Examin ation of the range between the BMD 10 and

BMDL 10 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 BMD 10 is 0.079 mg/kg and BMDL 10 is 0.052 mg/kg. This suggests that RBC AChE inhibition is more se nsitive in adult rats than the brain for oxamyl. The difference in BMD 10 and BMDL 10 for both adult brain (0.177/0.145=1.2x) and adult RBC (0.079/0.052=1.5x) is less than 2-fo ld as in the PND11 pups. This lower
adult RBC BMD 10 estimate influences the FQPA fact or for RBC. Specifically, this lower
adult RBC BMD 10 reduces the difference between adults and PND11 pups (0.079/0.059 = 1.338x).

The CCA study also demonstrates that the reco very half-life is slightly longer in the PND11 pups than in adults. The confidence in terval 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 NM C 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 neurot oxicity study (MRID 44254401). The data from the acute neurotoxicity study wa s inadvertently entered into the BMD files instead of the control data. Therefore, some of the ChE data from the acute neurotoxicity study wasPage 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 m odeling 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)

BMD 10 BMDL 10 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 BMD 10 s for brain and RBC are similar. However, the BMDL 10 for RBC (0.090 mg/kg) is lower than the brain

BMDL 10 (0.155 mg/kg), likely due to variability in the RBC data. A comparison of the
CCA data for adult brain BMD 10 (0.177 mg/kg) and BMDL 10 (0.144 mg/kg) is also very
similar to the combined adult brain BMD 10 (0.184 mg/kg) and BMDL 10 (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 fr om 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 BMDL 10 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 fact or derived from the ratio of BMD 10 of adult/PND11 pups may be artificially low based on the lower adult BMD 10 estimate from the CCA study.

The combined adult data also demonstrate similar recovery half-life times and tight
confidence intervals for brain and RBC. Th e adult RBC and brain half-life estimates are slightly shorter ( ≈ 1 hour) than the PND11 half-lif e estimates (1.5 to 2.5 hours).

c. Human Oral Study The oxamyl human toxicity study was performe d in 40 male subjects (19-39 years) in a dose-escalation fashion that provided dose-res ponse data for RBC AChE. AChE activity was measured every 15 minutes for the firs t two hours post-dosing, th en 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)

BMD 10 BMDL 10 Ratio ( BMD 10 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 dem onstrate less than a 1.5-fold difference
between the RBC BMD 10 and BMDL 10 (0.083 mg/kg/0.069 mg/kg= 1.2x). The human adult recovery half-life estimat e (2.37 hours) is similar to that of the juvenile RBC halflife estimate (2.54 hours). The confidence interv al of the adult human half-life is also
well within the confidence interval of the P ND11 RBC half-life. The interspecies factor
is based on the ratio of BMD 10 s for the adult combined RBC rat to adult RBC human (0.154 mg/kg/0.083 mg/kg = 1.86x).

4. Point of Departure Op tions 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 th e 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 th at 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 BMDL 10 in adult rats at the time (0.18 mg /kg). This older BMD analysis was based on an indentified data entry erro r in which the acute ne urotoxicity 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
CRA 3

PoD (mg/kg) BMDL 10 0.043 BMDL 10 0.039 BMDL 10 0.155 BMDL 10 0.090 BMDL 10 0.069 BMDL 10 0.069 BMDL 10 0.18

FQPA factor 1 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
factor 2 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 BMD 10 adult/BMD 10 pup from CCA study.

2 Interspecies factor based on ratio of BMD 10 rat/ BMD 10 human.

3 Revised NMC CRA (9/24/07) based on adult rat brain BMDL 10 from a 2006 analysis which did not incorporate the errors from th e control only study. The resulti ng interspecies factor was 3x.Page 6 of 13 Looking across the 6 options for the single chem ical 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 th e brain FQPA factor with the human RBC data also suggests an aPAD of 0.0026 mg/kg. Si nce brain data will never be available in humans, the brain FQPA from the rodent data would be protective of the brain compartment in humans. Op tion 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 BMD 10 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) th at was essentially 0.002 mg/kg. Therefore, based on this weight of the evidence approach to all the data available for oxamyl, the most appropri ate aPAD is 0.0026 mg/kg based on the human

RBC BMDL 10 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 compar ative cholinesterase study in which the sensitivity of the young to NMC’s is best eval uated has become available. Similar to results in comparative cholin esterase studies with other N -methyl carbamates, this comparative cholinesterase study revealed th at PND11 pups are more sensitive to oxamylPage 7 of 13 than adult rats. The FQPA factor is based on the ratio of the adult BMD 10 to PND11

BMD 10. Cholinesterase data from this one compar ative 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 pr egnant females since the developmental studies did not indicate suscepti bility. Therefore, for the single chemical risk assessment for oxamyl, the FQPA factor may be applied to the oral, dermal, and
inhalation assessments for thos e scenarios invol ving children.

6. Oxamyl Dose-Response Assessment

a. Acute Dietary
i. 1999 Acute Dietary The 1999 RED established an acute dietary poi nt of departure (PoD) for the general population based on the acute neur otoxicity 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 effect s, 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 extrapol ation. 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 (P oD) for the general population is based on the weight of the evidence of available AC hE data (rodent and human) for oxamyl. Therefore, the BMDL 10 of 0.069 mg/kg, based on RBC AC hE 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 BMD 10 to the PND11 brain BMD 10 both from the CCA study ( i.e. , 0.177/0.067= 2.640x). The inter-species fact or is not appropriate sin ce the PoD is based on human RBC AChE data. The intra-sp ecies 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 scen arios. 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 cholin esterase in females. The MOE was 100.Page 8 of 13 ii. 2010 Dermal PoD Since the 1999 RED, a BMD analysis that co mbined the AChE data from the same 4- week dermal adult rabbit study used in th e 1999 RED as well as an older rabbit dermal study (40827601; available at the time of 1999 RE D) 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 revi ew of this submission, HED considered the study protocols and ChE results from bot h dermal studies (D373514, TXR 0055348). As a result of this review, the newer 21-da y 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 c ould 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 t oxicity study in rabbits (MRID 40827601).

A BMD is preferred over a NOAEL and L OAEL approach since it provides the 10%
inhibition level based on AChE data from mu ltiple studies and eliminates the problem of dose spacing. Therefore, the BMD analys is provides the central estimate (BMD 10 ) and lower limit (BMDL 10 ) 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 resul ts for oxamyl (mg/kg)

BMD 10 BMDL 10 Brain 20.21 15.89

RBC 23.08 7.99

Comparison of the BMD 10 to BMDL 10 for both RBC and brain suggest that RBC ChE is slightly more variable (2 3.08/7.99=2.88x) than brain (20.21 /15.89=1.27x) (Table 6). The

BMD 10 s 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 occupationa l) 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 re sults 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 si ngle 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 shor t- 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 inhi bition 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 oxa myl, the RfC methodology is appropriate for extrapolating rats to humans . The RfC methodology and its a pplication here is discussed more below. Furthermore, since an aerosol and not a vapor was generated in this inhalation study, the RfC methodology can acc ount (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 we re measured at the end of the study at an appropriate acute time-point. The BMD an alysis indicates a robust dose-response relationship for assessing AChE activity with RBC and brain. The inhalation BMD results are given below in Table 7 (Setze r 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 BMDL 10 (mg/L)
Brain 0.005 0.004
RBC 0.002 0.0018

The NMC CRA relied on brain data and therefore the BMD 10 and BMDL 10 for the brain compartment. However, for the single chemi cal 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 br ain (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 vari ability in the data, then the RBC BMDL 10 of 0.0018 mg/L is appropriate as the PoD for the inhalation route of ex posure. This BMDL 10 results in 1.8 mg/m 3 which are appropriate for use in th e RfC methodology which is explained
further below.

Human data are not available for the oxamyl i nhalation 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) calcula tions. Compared to the methods previouslyPage 10 of 13 used by OPP, the dosimetry equations in th e RfC guidance more a ppropriately address different properties of gases and particle s, different propertie s of reactive and nonreactive compounds, and explicitly consider some differences in the structure of the respiratory tract between laboratory animal s 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 interm ediate-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 HE Cs 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 pa rticulate exposure concentration of an animal to the predicted inhalation part iculate 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 averag e work week for an occupational worker is 8 hours/day and 5 days/week.

Table 8: HEC Array for Acute Non-Occupation al Risk Assessment

Relevant Study BMD 10 or LOAEL (mg/L) BMDL 10 or NOAEL (mg/L) Da Dh Wa Wh RDDR HEC (mg/m 3 ) inter intra UF

Acute Inhalation Exposure

4 hr inhalation - Rat (46903529) SystemicRBC AChE 0.002 0.0018 (1.8 mg/m 3 ) 4 24 1 1 2.5 0.75 3 10

Table 9: HEC Array for Acute Occupational Risk Assessment

Relevant Study BMD 10 or LOAEL (mg/L) BMDL 10 or NOAEL (mg/L) Da Dh Wa Wh RDDR HEC (mg/m 3 ) inter intra UF

Acute Inhalation Exposure

4 hr inhalation - Rat (46903529) SystemicRBC AChE 0.002 0.0018 (1.8 mg/m 3 ) 4 8 1 1 2.5 2.25 3 10Page 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 hu man 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 Rout e-to-Route Extrapolations (Stasikowski Memo, 10-10-1998) was used to convert the oxa myl 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 absorp tion 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 ba sed on the RfC methodology developed by the
Office of Research and Devel opment (ORD) for the derivation of inhalation reference concentrations (RfCs) and human equivalent co ncentrations (HECs) for use in margin of exposure (MOE) calculations. Since the Rf C 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 10X 1 . Thus, the UF when using the RfC methodology is customarily 30X. The MO E of 30 is appropriate for adults, not

1 A 3X UF for interspecies extrapola tion 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 da ta to refine the intra- and inter-species factors for the dermal route of exposure.

As stated previously, due to th e rapid recovery of cholineste rase 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 analys is results in a dermal point of departure of 8.0 mg/kg based on RBC ChE inhibition. Based on this re vision, 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 occ upational) 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 fo r 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

Assessment 1

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 UF A =1x

UF H =10x FQPA SF=2.64x (brain) aRfD=0.0069

aPAD= 0.0026 (1⁄2 -life 2.5 hours) Human Study (MRID 44912301)

BMD 10 = 0.083 mg/kg

BMDL 10 = 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) UF A =10x

UF H =10x FQPA SF=1x MOE = 100 (adult) 21-day dermal rabbit study (40827601)

RBC BMD 10 is 23.1 mg/kg

RBC BMDL 10 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/m 3 or 0.39 mg/kg

RBC Non-Occupational:

HEC= 0.75 mg/m 3 or 0.13 mg/kg UF A =3x

UF H =10x FQPA SF= 1x MOE = 30 (adult) Acute inhalation rat (45155801)

RBC BMD 10 = 0.002 mg/L

RBC BMDL 10 = 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. UF A = extrapolation from animal to human (interspecies).

UF H = 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. HE C = Human Equivalent Concentration. RDDR = regional deposited dose ratio.