NAC Proposed 1: June 2009 1

2
3

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## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 5



## FOR 6



## OXAMYL 7


## (CAS Reg. No. 23135-22-0) 8

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10 11

12 

## PROPOSED 13

14OXAMYL NAC Proposed 1: June 2009/ Page 2 of 36

1
PREFACE 2
3 Under the authority of the Federal Adviso ry Committee Act (FACA) P. L. 92-463 of 4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 5 Substances (NAC/AEGL Committee) has been es tablished to identify, review and interpret 6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 7
chemicals. 8
9 AEGLs represent threshold exposure limits for the general public and are applicable to 10 emergency exposure periods ranging from 10 minut es to 8 hours. Three levels – AEGL-1, 11 AEGL-2 and AEGL-3 – are developed for each of five exposure periods (10 and 30 minutes, 1 12 hour, 4 hours, and 8 hours) and are distinguished by va rying degrees of severity of toxic effects. 13
The three AEGLs are defined as follows: 14
15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 16 cubic meter [ppm or mg/m 3 ]) of a substance above which it is predicted that the general 17 population, including susceptible individuals, could experience notable discomfort, irritation, or 18 certain asymptomatic, non-sensory effects. Ho wever, the effects are not disabling and are 19 transient and reversible upon cessation of exposure. 20

21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 22 which it is predicted that the general population, including susceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 24
to escape. 25
26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 27 which it is predicted that the general population, including susceptible individuals, could 28 experience life-threatening health effects or death. 29
30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 31 mild and progressively increasing but transi ent and nondisabling odor, taste, and sensory 32 irritation or certain asymptomatic, non-sensory eff ects. With increasing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 34 severity of effects described for each corresponding AEGL. Although the AEGL values 35 represent threshold levels for the general public, including susceptible subpopulations, such as 36 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 37 that individuals, subject to unique or idiosyncratic responses, could experience the effects 38 described at concentrations below the corresponding AEGL. 39
40OXAMYL NAC Proposed 1: June 2009/ Page 3 of 36

TABLE OF CONTENTS 1

PREFACE........................................................................................................................ .............................2 2

SUMMARY........................................................................................................................ ..........................6 3

1. INTRODUCTION................................................................................................................ ................7 4

2. HUMAN TOXI CITY DATA......................................................................................................... ......8 5

3. ANIMAL TOXI CITY DATA........................................................................................................ ......9 6

3.1. Acute Lethality ........................................................................................................... .................9 7

3.2. Acute Non-Lethal Toxicity................................................................................................. .......11 8

3.3. Repeat-Exposure Studies................................................................................................... ........11 9

3.4. Neurotoxicity............................................................................................................. ................11 10

3.5. Developmental/Reproductive Toxicity......................................................................................1 2 11

3.6. Genotoxicity .............................................................................................................. ................12 12

3.7. Subchronic and Chronic Toxicity/Carcinogenicity ...................................................................13 13

3.8. Summary................................................................................................................... .................13 14

4. SPECIAL CONS IDERATIONS ...................................................................................................... ..14 15

4.1. Metabolism and Disposition................................................................................................ ......14 16

4.2. Mechanism of Toxicity..................................................................................................... .........14 17

4.3. Structure-Activity Relationships .......................................................................................... .....15 18

4.4. Other Relevant Information................................................................................................ .......16 19 4.4.1. Species Variability ..................................................................................................... ...........16 20 4.4.2. Susceptible Populations ................................................................................................. .......16 21 4.4.3. Concentration-Exposur e Duration Relationship ...................................................................16 22 4.4.4. Concurrent Exposure Issues.............................................................................................. ....17 23

5. DATA ANALYSIS FOR AEGL-1 .................................................................................................... 17 24

5.1. Summary of Human Data Relevant to AEGL-1........................................................................17 25

5.2. Summary of Animal Data Relevant to AEGL-1........................................................................17 26

5.3. Derivation of AEGL-1...................................................................................................... .........17 27

6. DATA ANALYSIS FOR AEGL-2 .................................................................................................... 18 28

6.1. Summary of Human Data Relevant to AEGL-2........................................................................18 29

6.2. Summary of Animal Data Relevant to AEGL-2........................................................................18 30

6.3. Derivation of AEGL-2...................................................................................................... .........18 31OXAMYL NAC Proposed 1: June 2009/ Page 4 of 36

7. DATA ANALYSIS FOR AEGL-3 .................................................................................................... 18 1

7.1. Summary of Human Data Relevant to AEGL-3........................................................................18 2

7.2. Summary of Animal Data Relevant to AEGL-3........................................................................18 3

7.3. Derivation of AEGL-3...................................................................................................... .........18 4

8. SUMMARY OF AEGLs............................................................................................................ ........19 5

8.1. AEGL Values and Toxicity Endpoints......................................................................................19 6

8.2. Comparison with Other Standards and Guidelines....................................................................19 7

8.3. Data Adequacy and Research Needs .........................................................................................2 1 8

9. REFERENCES.................................................................................................................. .................21 9

APPENDIX A: Time-Scaling Calculation for Oxamyl AEGLs ................................................................24 10

APPENDIX B: Derivati on of Oxamyl AEGLs........................................................................................ ..25 11

APPENDIX C: Benchmark Concentra tion Calculations for Oxamyl........................................................28 12

APPENDIX D: Category Graph of AE GL Values and Toxicity Data ......................................................32 13

APPENDIX E: Derivation Summary for Oxamyl AEGLs ........................................................................34 14OXAMYL NAC Proposed 1: June 2009/ Page 5 of 36

LIST OF TABLES 1

2 S 1. Summary of AE GL Values for Ox amyl....................................................................................... ..............7 3

TABLE 1. Chemical and Physical Pr operties ...................................................................................... ........................8 4 TABLE 2. Mortality of Rats Exposed to Oxamyl for 1 or 4 Hours .................................................................. .........10 5

TABLE 3. Adult Rat and Human BMD 10 and BMDL 10 Values for Cholinesterase Activity Inhibition by N -Methyl 6

Carbamate Pesticid es (Oral Dosing) ............................................................................................. ...........15 7

TABLE 4. AEGL-1 Va lues for Oxamyl .............................................................................................. ......................17 8

TABLE 5. AEGL-2 Va lues for Oxamyl .............................................................................................. ......................18 9

TABLE 6. AEGL-3 Va lues for Oxamyl .............................................................................................. ......................19 10 TABLE 7. Summary of AEGL Values ................................................................................................ ......................19 11

TABLE 8. Standards and Guidelines for Ox amyl................................................................................... ...................20 12 13
14 15OXAMYL NAC Proposed 1: June 2009/ Page 6 of 36

SUMMARY 1

2 Oxamyl (CAS No. 23135-22-0) is a crystalline solid N -methyl carbamate insecticide with 3 a slightly sulfurous odor. Oxamyl is used as an insecticide, nematicide, and acaricide on field 4 crops such as vegetables, fruits, and ornamentals. It is sold as a granule formulation or as a 5 liquid formulation under the trade name VydateTM. Solid oxamyl is very stable and has a low 6 vapor pressure. Oxamyl is manufactured commercially by chlorination of the oxime of methyl 7 glycolate, reaction of that product with meth anethiol and alkali, followed by reaction with 8 dimethylamine, and conversion to the carbamate with methyl isocyanate. Approximately 9 800,000 pounds of active ingredient are applied annually in the United States. Application to 10 cotton fields accounts for most of the usage. 11

12 Oxamyl and other carbamate pesticides are neurotoxic in that they are inhibitors of the 13 enzyme acetylcholinesterase. Inhibition of acetylcholinesterase, responsible for termination of 14 the biological activity of the neurotransmitter acetylcholine at various nerve endings, produces 15 sustained stimulation of electrical activity. De pending on the concentration administered, signs 16 following acute exposure of rats to oxamyl may include facial fasciculations, tremors, salivation, 17 lacrimation, gasping and convulsions. In humans, inhibition of erythrocyte acetylcholinesterase 18 activity is used as a biomarker of methyl carbama te exposure and effects. No inhalation studies 19 involving human subjects were located. Given that methyl carbamate pesticides do not have a 20 port of entry effect, are expected to be rapidly absorbed, and do not require activation, relative 21 acetylcholinesterase activity inhibition levels measured from oral studies with humans and 22 juvenile and adult rats were used to derive interspecies and intraspecies uncertainty factors. 23

24 The recent well-conducted study of O’Neil (2000, reviewed in U.S. EPA 2000) with rats 25 inhaling oxamyl dust was chosen as the key study to derive AEGL-1 values. In that study, male 26 and female rats inhaled 4.9 mg/m 3 of oxamyl dust for 4 hours. Erythrocyte acetylcholinesterase 27 activity was inhibited by an average 28.5% and brain cholinesterase by an average 12% (sexes 28 combined). Erythrocyte acetylcholinesterase activity inhibition of that magnitude may result in 29 transient symptoms of discomfort in humans. Exposure to 24 mg/m 3 for 4 hours resulted in 30 average erythrocyte and brain cholinesterase ac tivity inhibition of 67-73%. Following exposure, 31 rats showed ocular/nose discharge, diarrhea, tremors, and lethargy. Signs were similar in the 32 control and 4.9 mg/m 3 exposure groups. The 4-hour 4.9 mg/m 3 value was divided by inter- and 33 intraspecies uncertainty factors of 3 and 3.48, respectively, for a total of 10. The chemical34 specific uncertainty factors were calculate d by U.S. EPA (2007b). Their oxamyl-specific 35 interspecies inhalation uncertainty factor was based on differences in modeled values for 36 erythrocyte cholinesterase activity inhibition between rats and humans following oral dosing. 37 Based on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 juvenile 38 rats and adult rats, the U.S. EPA calculated an uncertainty factor of 3.48 to protect sensitive 39 young. The resulting 0.49 mg/m 3 value was time-scaled (C n x t = k) from the 4-hour data point 40 using an n value of 1.6 derived from three letha lity studies involving exposure durations of 1 and 41
4 hours. 42
43
No studies that addressed effects consistent with the definition of the AEGL-2 tier were 44 found. The concentration-response curve for lethality in rats is steep. As shown by the study of 45 Kelly (2001), mortality went from 0% at 50 mg/m 3 to 100% when concentration was increased 46OXAMYL NAC Proposed 1: June 2009/ Page 7 of 36

2.4-fold (120 mg/m 3 ). Therefore, according to Standard Operating Procedures (NRC 2001), the 1 AEGL-2 values were derived by dividing the AEGL-3 values by 3. 2
3 The study of Kelly (2001) with male and female rats was chosen as the basis for 4 development of AEGL-3 values. The study was conducted according to U.S. EPA guidelines. 5
The calculated 4-hour BMCL 05 for lethality for oxamyl dust was 22 mg/m 3 . The 22 mg/m 3 value 6 was divided by inter- and intraspecies uncertainty factors of 3 and 3.48 for a total of 10. U.S. 7 EPA (2007b) derived an interspecies uncertainty factor of 3 for oxamyl based on differences in 8 values for erythrocyte acetylcholinesterase activity inhibition between rats and humans. Based 9 on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 juvenile rats 10 and adult rats, the U.S. EPA calculated an uncertainty factor of 3.48 to protect sensitive young. 11 The combined (rounded) uncertainty factor is 10. Although female rats appear to be slightly 12 more sensitive to the toxic effects of oxamyl than male rats, the combined data with application 13 of an uncertainty factor that protects sensitive juveniles provides a reasonable estimate of 14 lethality. Values were time-scaled (C n x t = k) from the 4-hour data point using an n value of 15 1.6. The n value of 1.6 was based on three studies that encompassed exposure durations of one 16
and four hours. 17
18
The calculated values are listed in the table below. 19
20

S 1. Summary of AEGL Values for Oxamyl

Classification 10-min 30-min 1-h 4-h 8-h Endpoint (Reference)

AEGL

B 1 (Nondisabling) 3.6 mg/m 3 1.8 mg/m 3 1.2 mg/m 3 0.49 mg/m 3 0.32 mg/m 3 Slight symptoms of cholinesterase activity
inhibition – rat (O’Neil 2000; U.S. EPA 2000)

AEGL

B 2 (Disabling) 5.3 mg/m 3 2.7 mg/m 3 1.8 mg/m 3 0.73 mg/m 3 0.47 mg/m 3 AEGL-3 values divided by 3 based onsteep concentrationresponse curve AEGL

B 3 (Lethal) 16 mg/m 3 8.2 mg/m 3 5.3 mg/m 3 2.2 mg/m 3 1.4 mg/m 3 4-hour BMCL 05 for lethality– rat data (Kelly 2001)

21

22
1. INTRODUCTION 23

24 Technical oxamyl (CAS No. 23135-22-0) is a crystalline solid N -methyl carbamate 25 insecticide with a slight sulfurous odor. Oxamyl is used as an insecticide, nematicide, and 26 acaricide on field crops such as vegetables, fruits, and ornamentals. It is sold under the trade 27 names VydateTM and Vydate LTM. Technical grade oxamyl contains 89% a.i. (active ingredient). 28 It is registered for use as liquid formulations (24 and 42% a.i.) and as a technical solid (42% 29 a.i.). Vydate L is a water soluble liquid containing 24% oxamyl (Kennedy 1986a; HSDB 2004; 30 U.S. EPA 2007a). Oxamyl is also commercially available as a granule formulation (10% a.i.) 31 and as technical material in cyclohexanone/water at 42% a.i. Solid oxamyl is very stable (IPCS 32 1983). The chemical and physical properties of oxamyl are listed in Table 1. 33OXAMYL NAC Proposed 1: June 2009/ Page 8 of 36

1 Oxamyl is manufactured commercially by chlorination of the oxime of methyl glycolate, 2 reaction of that product with methanethiol and alkali, followed by reaction with dimethylamine, 3 and conversion to the carbamate with methyl isocyanate (HSDB 2004). Approximately 800,000 4 pounds of active ingredient are applied annually in the United States (U.S. EPA 2007a). Cotton 5 accounts for most of the usage. 6

7

TABLE 1. Chemical and Physical Properties

Parameter Value Reference Synonyms Methyl N’N’-dimethyl- N

- [(methylcarbamoyl)-oxy]-1- thiooxamimidate; 2-(dimethylamino)- N

- [[(methylamino)]oxy]-2- oxoethanimodothioic acid methyl ester; N’N’-dimethyl- N

- [(methylcarbamoyl)oxy]-1-thiooxaminidic acid methyl ester; N,Ndimethyl- ά -methylcarbamoyloxyiminoά -(methylthio)acetamide: methyl 1- (dimethylcarbamoyl)- N

- (methylcarbamoyloxy)thioformimidate; thioxamyl; DPX-1410; Vydate O’Neil et al. 2001;

U.S. EPA 2007a
RTECS 2008

Chemical formula C 7 H 13 N 3 O 3 S O’Neil et al. 2001 Molecular weight 219.26 O’Neil et al. 2001 CAS Reg. No. 23135-22-0 O’Neil et al. 2001 Physical state crystalline solid O’Neil et al. 2001 Solubility in water 280 g/L O’Neil et al. 2001 Vapor pressure 0.00023 mm Hg at 20-25oC HSDB 2004 Vapor density (air =1) 0.97 g/cm 2 at 25oC HSDB 2004 Liquid density (water =1) No data Melting point 100-102oC O’Neil et al. 2001 Boiling point Decomposes above melting point HSDB 2004 Flammability limits in air Not available Conversion factors 1 ppm = 8.97 mg/m 3 1 mg/m 3 = 0.11 ppm Calculated

8
9
2. HUMAN TOXICITY DATA 10

11
No inhalation studies other than accidental exposures were located. These accidental 12 exposures lacked information on concentration and exposure duration. No occupational 13 monitoring data were presented by U.S. EPA (2007a). An oral dosing study was conducted by 14 McFarlane and Freestone (1999; reviewed in U.S. EPA 2005). The Human Studies Review 15 Board (HSRB 2006) reviewed the study and found it met ethical considerations (required by 16 EPA’s Human Subjects Protection Rule). Forty healthy male subjects, ages 19-39 years, in 17 groups of five, ingested a gelatin capsule of oxamyl at doses of 0.005, 0.015, 0.03, 0.06, 0.09, or 18 0.15 mg a.i./kg body weight. Ten subjects received a placebo capsule. The dose was 19 accompanied with a light breakfast. Clinical symptoms and signs were recorded pre-dose and at 20 set times post-dose. Plasma and erythrocyte cholinesterase activity were assayed pre-dose and at 21 set times post-dose. Clinical signs were reported by three subjects in the placebo group, three 22 subjects in the 0.015 mg/kg dose group, one subject in the 0.03 mg/kg dose group, and one 23OXAMYL NAC Proposed 1: June 2009/ Page 9 of 36

subject in the 0.15 mg/kg dose group. Incidences of these signs did not show a dose-response 1 relationship and did not correspond with cholinesterase activity inhibition in the dosed groups. 2 The time of peak plasma and erythrocyte cholinesterase activity inhibition was 30-60 minutes 3 after dosing, with recovery to baseline by 3 hours post-dose. Based on a 7% inhibition of 4 erythrocyte cholinesterase activity, the U.S. EPA set the LOAEL at 0.09 mg/kg. The NOAEL 5 was 0.06 mg/kg. Erythrocyte cholinesterase activity was inhibited by an average of 28% at 45 6 minutes post-dose in the 0.15 mg/kg dose group. 7
8
3. ANIMAL TOXICITY DATA 9
10 Using standard protocols, oxamyl has been tested for ocular and dermal irritation in the 11 rabbit and dermal sensitization in the guinea pig (IPCS 2002). Oxamyl was not considered an 12
ocular or dermal irritant and did not induce skin sensitization. The oral LD 50 in male and female 13 rats is 2.5-3.1 mg/kg (Kennedy 1986a). 14
15 3.1. Acute Lethality 16
17 All inhalation studies were conducted with rats (Table 2). In these studies, atmospheres 18 of oxamyl were generated as dust or liquid aerosol. In an early study, groups of six young male 19 ChR-CD rats inhaled 95% pure oxamyl dust, h ead-only, at concentrations of 140, 160, 180, or 20 210 mg/m 3 for one hour (Kennedy 1986a; see also DuPont 1969a for details of the study). 21 Groups of six young female ChR-CD rats inhaled oxamyl (95% a.i.) at analytically-determined 22 concentrations of 100, 120, or 140 mg/m 3 , head-only, for one hour. All rats were two months 23 old at initiation of the study. Particles were suspended by blowing air through a high velocity 24 glass jet submerged in a mechanically-stirred reservoir of the test dust. Particle size, determined 25 by cascade impactor sampling, averaged 3.5±2.1μ mass median diameter. All surviving rats 26 were observed for 14 days post-exposure. Duri ng exposure, clinical signs included facial 27 fasciculations, exophthalmos, lacrimation, red discharge around the nose and eyes, salivation, 28 and gasping. Survivors lost weight during the fi rst day, but showed normal growth thereafter. 29
Calculated 1-hour LC 50 values were 170 mg/m 3 for male rats and 120 mg/m 3 for female rats. 30
31 In a 4-hour study, groups of six male ChR-CD rats inhaled oxamyl dust (95% a.i.), head32 only, at analytically-determined concentrations of 20, 53, 66, 77, or 90 mg/m 3 (Kennedy 1986a; 33 DuPont 1969b). Particles were suspended in a 20-liter glass cylinder using a cyclone generator. 34 Particle size (3.5±2.1μ) was determined by cascade impactor sampling. Male rats exposed to 20 35 mg/m 3 for 4 hours were sacrificed at 1, 2, and 7 days (two rats each day). Major tissues and 36 organs of these rats were examined grossly and microscopically. Signs displayed during 37 exposure were intense salivation, facial fasciculations, red discharge around the nose, 38 lacrimation, exophthalmos, difficulty in breathing, and gasping. Signs were less severe at the 39 lower concentrations. Deaths generally occurred within one day post-exposure. Following 40 exposure, surviving rats were pale in color and lost up to 7% body weight. These signs resolved 41 with no delayed deaths occurring. Except for mild congestion of some organs, results of the 42 pathologic examinations of rats exposed to 20 mg/m 3 were unremarkable on all post-exposure 43 days. The four-hour LC 50 value for male rats was 64 mg/m 3

. 44
45 In a GLP study that followed U.S. EPA guidelines for acute inhalation studies, groups of 46 5 male and 5 female Crl:CD rats were expose d, nose-only, to technical oxamyl (98% w/w) dust 47OXAMYL NAC Proposed 1: June 2009/ Page 10 of 36

at concentrations of 50, 54, 65, or 120 mg/m 3 for 4 hours (Kelly 2001). Chamber atmospheres of 1 oxamyl were generated by suspending the particulate test substance with a jetmill. The test 2 substance was metered into the jetmill with a bin feeder. Filtered, high-pressure air carried the 3 atmosphere from the jetmill into a 29-L exposure chamber. Chamber concentrations were 4 controlled by varying the test substance feed rate. Atmosphere concentrations were determined 5 by gravimetric analysis; HPLC analysis was used to determine the percentage of active 6 ingredient on the gravimetric filters. Particle size (mass median aerodynamic diameter ) ranged 7 from 3.2-4.2 μ. 8
9 Concentration-related deaths occurred either during exposure or within 2 days of 10 exposure (Kelly 2001). All rats died at the highest exposure. The LC 50 for the sexes combined 11 was 56 mg/m 3 . During exposure, red nasal discharge, gasping, and salivation were observed. 12 There was a diminished response to an alerting stimulus. Immediately after exposure and during 13 recovery, clinical signs included lethargy, decreased muscle tone, tremors, spasms, 14 fasciculations, abnormal posture, abnormal gait, high carriage, and ataxia. Some clinical signs 15 were seen in all groups. All clinical signs returned to normal in the second week after exposure. 16 At necropsy, gross observations were unremarkable. 17
18 Groups of five male and five female CrL: CD rats inhaled aerosol atmospheres (not 19 further defined) of a proprietary mixture of oxamyl at concentrations of 160, 220, 240, or 510 20 mg/m3 for 4 hours (U.S. EPA 1997). Chamber concentrations were based on measured aerosol 21 concentrations and the reported purity of the active ingredient in the formulation. Rats died 22 either during exposure or within three days following exposure. Fractional mortalities were 23 1/10, 2/10, 9/10, and 10/10 at the lowest through highe st concentrations, respectively (gender not 24 provided). Tremors and abnormal gait/mobility were observed in most surviving rats in the 160 25 and 220 mg/m 3 groups. Other clinical signs included gasping, lung noise, irregular respiration, 26 lethargy, hunched posture, and diarrhea. No further details were provided in the summary 27
document. 28
29
30

TABLE 2. Mortality of Rats Exposed to Oxamyl for 1 or 4 Hours
Exposure Duration/
Gender Concentration (mg/m 3 ) Mortality LC 50 (mg/m 3 ) Reference

Dust or Powder Form 1 hour (males) 140

160
180
210 0/6
2/6
4/6
5/6 170 DuPont 1969a; Kennedy 1986a

1 hour (females) 100

120
140 1/6
3/6
5/6 120 DuPont 1969a; Kennedy 1986a

4 hours (both sexes) 4.9

24 0/20
0/20 ─ O’Neil 2000;

U.S. EPA 2000 4 hours (males) 20

53
66

77
90 0/6
1/6
3/6
5/6
6/6 64 Dupont 1969b; Kennedy 1986a

4 hours (both sexes) 50

54 males: 0/5; females: 2/5 males: 1/5; females: 5/5 56 Kelly 2001OXAMYL NAC Proposed 1: June 2009/ Page 11 of 36

65
120 males: 3/5; females: 4/5 males: 5/5; females: 5/5

Aerosol
4 hours (both sexes) 160

220
240
510 1/10
2/10
9/10
10/10 ~230 U.S. EPA 1997

1 3.2. Acute Non-Lethal Toxicity 2
3 A study with oxamyl dust addressed non-lethal concentrations (Table 2). Two groups of 4 rats, 10 per sex per group, inhaled 0, 4.9 or 24 mg/m 3 aerosolized oxamyl dust, nose-only, for 4 5 hours (O’Neil 2000; reviewed in U.S. EPA 2000). Test atmospheres were measured 6 gravimetrically. Particle size ranged from 0.82 to 1.2 μ. Sacrifice took place immediately after 7 exposure for cholinesterase activity determination. No deaths occurred during exposure. Wet 8 stains, ocular/nose discharge and diarrhea were seen in all rats including the control groups. 9 Tremors and lethargy were seen in the exposed groups, but incidences in the 4.9 mg/m 3 group 10 were similar to those of the control groups (incidence data not reported). Compared to the pre11 exposure values, plasma, erythrocyte and brain cholinesterase activity in males in the 4.9 mg/m 3 12 group were inhibited by 12, 28, and 15%, respectively. Respective values for males in the 24 13 mg/m 3 group were 72, 72, and 68%. Compared to the control values, plasma, erythrocyte and 14 brain cholinesterase activity in females at 4.9 mg/m 3 were inhibited by 6.5, 29, and 9%, 15 respectively. Respective values for females in the 24 mg/m 3 group were 76, 73, and 67%. 16
17 3.3. Repeat-Exposure Studies 18
19 No repeat-exposure inhalation studies were locat ed. Repeated-dose oral studies with the 20 rat show that oxamyl does not accumulate nor do the clinical signs of response change 21 dramatically following multiple exposures at the same concentration (Kennedy 1986b; IPCS 22 2002; HSDB 2004). 23

24 3.4. Neurotoxicity 25
26 The studies described in Section 3.1 show that oxamyl is neurotoxic. Clinical signs 27 included lethargy, decreased muscle tone, tremors, spasms, facial fasciculations, lacrimation, 28 salivation, abnormal posture and gait, and ataxia. See Section 4.1 for the mode of action of 29
carbamate insecticides. 30
31 In a study of gavage administration of oxamyl to male Long-Evans rats, motor activity 32 in the period 15 to 35 minutes post-dosing was a reliable predictor of brain and erythrocyte 33 cholinesterase activity inhibition (McDaniel et al. 2007). Doses were 0, 0.07, 0.10, 0.50, 1.00, 34 and 1.50 mg/kg. Brain and erythrocyte acetylcholinesterase activity and motor activity were 35 unaffected at doses of 0.07 and 0.10 mg/kg. Inhibited cholinesterase activity and decreased 36 motor activity were dose related at >0.10 mg/kg, with brain acetylcholinesterase activity falling 37 to approximately 40% of the control value and erythrocyte acetylcholinesterase activity and 38 horizontal and vertical motor activity inhibited to <40% of control. One rat in the 1.00 mg/kg 39 dose group and two rats in the 1.50 mg/kg dose group showed subtle cholinergic signs. 40

41OXAMYL NAC Proposed 1: June 2009/ Page 12 of 36

3.5. Developmental/Reproductive Toxicity 1

2
No inhalation studies were conducted that a ddressed developmental/reproductive toxicity 3 of oxamyl. Reproductive and developmental toxi city studies that used the oral route of 4 administration were reviewed in Kennedy ( 1986b), IPCS (2002) and HSDB (2004). These 5 studies are summarized here, demonstrating that oxamyl is not a developmental or reproductive 6 toxicant even at doses that are maternally toxic. In a two-generation reproductive toxicity study, 7 male and female CrL-CD rats ingested oxamyl in the diet at doses of 0, 25, 75, or 15.8 ppm 8 (approximately 0, 1.7, 5.2, or 11.6 mg/kg/day for males and 0, 2.0, 6.6, or 15.8 mg/kg/day for 9 females). F 0 rats were mated 74 days after the beginning of treatment to produce the F 1 10 generation. The F 1 generation was treated for at least 105 days after weaning; dietary 11 administration continued until weaning of the F 2 generation. The NOAEL for parental toxicity 12 (F 0 and F 1 parental generation) was 25 ppm. Decr eases in body weight, body weight gain, food 13 consumption and efficiency, and increased relative testis weight were seen at 75 ppm. The 14 NOAEL for developmental toxicity was also 25 ppm oxamyl in the diet. Reduced pup weight 15 was seen at 75 ppm during lactation. The NOAEL for reproductive toxicity was 75 ppm. 16
17 Similar results were reported in a three-generation oral reproduction study with male and 18 female CrL-CD rats. Dietary concentrations were 0, 50, 100, or 150 ppm. Oxamyl had no effect 19 on the number of pregnancies or on gestation or fertility indexes. Dose-dependent reductions in 20 litter size and body weight of weanlings at 100 and 150 ppm were observed consistently 21 throughout the study. Individual data were not provided. 22
23 In a developmental toxicity study, groups of 25 pregnant Charles River CD BR rats 24 received doses of 0, 0.2, 0.5, 0.8, or 1.5 mg/kg dur ing gestation days 7-16. Doses were 25 administered by gavage. The dams were killed on day 22 of gestation and the dams and fetuses 26 were examined. There were no maternal deaths or abnormal gross changes in the dams. 27 Maternal toxicity consisting of reduced body weight and reduced food consumption were 28 observed at 0.8 mg/kg and above, and signs of c holinesterase inhibition were observed at 1.5 29 mg/kg. Fetal body weight was decreased at 0.8 mg/kg and above. There were no fetal 30
malformations. 31
32 In a developmental toxicity study, groups of 17 pregnant New Zealand rabbits were 33 gavaged with oxamyl at doses of 0, 1, 2, or 4 mg/ kg/day on days 6-19 of gestation. On gestation 34 day 22, all surviving dams were sacrificed and all fetuses were examined for malformations. 35 One doe each in the 1 and 4 mg/kg/day groups died; these deaths were attributed to gavage error. 36 Maternal body weight was reduced at 2 and 4 mg/kg/day, but necropsies were unremarkable. 37 Although fetal resorptions were increased at 2 and 4 mg/kg/day, no fetal parameters (body 38 weight, sex ratio, crown-rump length, or external or internal malformations) were statistically 39 significantly affected. 40

41 3.6. Genotoxicity 42
43 Oxamyl has been tested in a range of in vitro genotoxicity assays (IPCS 2002; HSDB 2004). 44 No studies addressed genotoxicity in vivo . Most assays were conducted with and without 45 metabolic activation. Assay results were negative for reverse mutation in Salmonella 46 typhimurium (TA97a, TA98, TA100, TA1535, TA1537) and Escherichia coli WP2 uvrA. 47OXAMYL NAC Proposed 1: June 2009/ Page 13 of 36

Results were negative for chromosomal aberrations and gene mutations in Chinese hamster 1 ovary cells, chromosomal aberrations in human lymphocytes, and unscheduled DNA synthesis in 2 rat hepatocytes. Test concentrations ranged up to 1200 μmol/L. Cytotoxicity was observed at 3 the higher concentrations. 4

5 3.7. Subchronic and Chronic Toxicity/Carcinogenicity 6

7 Subchronic and chronic studies employed the dietary route of administration (Kennedy 8 1986b; IPCS 2002; HSDB 2004). These studies are onl y briefly described here in order to show 9 the mode of action and species variability. Male and female CrL-CD Rats fed a diet containing 10 oxamyl at concentrations of 0, 50, 100, 150, or 500 ppm for 90 days showed signs of 11 cholinesterase activity inhibition and body weight loss within 2 days at 500 ppm. Dietary 12 administration at 100 or 150 ppm resulted in reduced body weight gain (up to 7%) without other 13 clinical signs. No effects were observed at 50 ppm. Feeding of oxamyl at 100 or 150 ppm for 14 two years also resulted in depressed weight gain. Cholinesterase activity was inhibited only 15 during the first week of feeding at 150 ppm. There was no tumor response. The NOAEL was 50 16 ppm (approximately 5 mg/kg/day). 17
18 In a similar 90-day feeding study, concentrations of 0, 10, 30, or 250 ppm were 19 administered in the diet to male and female Crl:CD rats (U.S. EPA 1998). The systemic LOAEL 20 was 250 ppm based on lower body weight. The LOAEL for neurotoxicity was based on 21 decreases in brain, plasma, and erythrocyte cholinesterase activity inhibition, and impaired 22 performance in a Functional Observational Battery at 250 ppm. The NOAEL was 30 ppm. 23 These dietary concentrations corresponded to 2.1 and 2.4 mg/kg/day (NOAELs for males and 24 females, respectively) and 14.9 and 19.9 mg/kg/day (LOAELs for males and females, 25 respectively). 26
27 In a two year feeding study, male and female CrL-CD-1 mice were administered diets 28 containing 0, 25, 50, or 100 ppm (the latter reduced to 75 ppm due to early mortalities). Body 29 weight of mice fed 50 or 75 ppm was lower than that of controls during the first 6 months of the 30 study. No other toxic response was seen. There was no evidence of a tumorigenic response. 31 The NOAEL was 25 ppm in the diet (approximately 2.5 mg/kg/day). 32
33 Dogs fed oxamyl at 150 ppm for 2 years showed some clinical chemistry changes but no 34 inhibition of cholinesterase activity. There were no deaths and no histological changes in major 35 tissues and organs attributed to the test material. The NOAEL was 100 ppm in the diet 36 (approximately 2.5 mg/kg/day). 37
38 3.8. Summary 39
40 Acute inhalation lethality studies were conducted with the rat. Toxicity was dependent 41 on the form of the administered chemical, with the dust being more toxic than the aerosol. The 42
1- and 4-hour LC 50 values for male rats inhaling the dust were 170 and 64 mg/m 3 , respectively. 43 Female rats were more sensitive to the inhalation toxicity of oxamyl dust. The 1- and 4-hour 44
LC 50 values for female rats were 120 and <50 mg/m 3 , respectively. The 4-hour LC 50 value for 45 both sexes combined was 56 mg/m 3 (Kelly 2001). During exposure, rats showed signs indicative 46 of acetylcholinesterase activity inhibition. The 4-hour LC 50 for an aerosol of oxamyl particulates 47OXAMYL NAC Proposed 1: June 2009/ Page 14 of 36

was approximately 230 mg/m 3 (U.S. EPA 1997). The low vapor pressure of oxamyl (2.3 x 10 -4 1 mm Hg at 20-25 oC) makes vapor studies at ambient temperatures impractical. 2
3 No evidence of teratogenicity was observed in either the rat or rabbit treated in the diet 4 with oxamyl (up to 150 ppm) even in the presence of maternal toxicity. A range of genotoxicity 5 assays all provided negative results. In 2-year feeding studies with the dog, rat, and mouse at 6 concentrations that approached toxic as indicat ed by reduced weight gain, there was no evidence 7 of a tumorigenic response. 8
9
4. SPECIAL CONSIDERATIONS 10 4.1. Metabolism and Disposition 11

12 Inhalation metabolism studies with oxamyl were not located. The N -methyl carbamates 13 do not have a port of entry effect, are expected to be rapidly absorbed, and do not require 14 activation (U.S. EPA 2007b). Therefore, relative potency can be estimated from oral studies. 15 Unlike some organophosphate pesticides that are metabolized by A-esterases which show great 16 inter-individual variation, the biotransformation of the carbamate pesticides does not involve A17
esterases. Studies of biotransformation in vivo and in vitro following administration by the oral 18 route or intraperitoneal injection showed that oxamyl is metabolized in rats and mice via two 19 major pathways: non-enzymatic hydrolysis to the oxime (methyl 2-dimethylamino)- N-hydroxy20 2-ethanimidothioate or DMTO) and enzymatic conversion to dimethylamine(oxo)acetic acid 21 (DMOA) (Harvey and Han 1978; IPCS 1983; 2002). Incubation of 14 C-labeled oxamyl with rat 22 or mouse liver homogenate or liver microsomes showed the major fraction of label associated 23 with the parent compound. Metabolites indicated metabolism by the routes described above. 24
25 When mice were injected intraperitoneally with 14 C-labeled oxamyl, urinary metabolites 26 consisted of the parent compound (16%), DMTO (44%), and a number of other metabolites, 27 many not identified (Chang and Knowles 1979). In rats treated orally, most radioactivity was 28 excreted in the urine (Harvey and Han 1978; IPCS 2002). Most of the radioactivity in urine and 29 feces was recovered as polar conjugates of DMTO, DMOA, and several other metabolites. 30 According to Costa (2008), most metabolites of carbamic acid ester pesticides are devoid of 31 biological activity. 32
33 Metabolism is fairly rapid as indicated by recovery of brain and erythrocyte 34 cholinesterase activity following inhibition in rats. In adult Long-Evans rats dosed orally with 1 35 mg/kg oxamyl, brain and erythrocyte cholinesterase activity were approximately 50 and 20% of 36 control, respectively at 0.5 hours post-dose; activities in both compartments returned to control 37 values by 4 hours post-dosing (Padilla et al. 2007). The half-lives for recovery from erythrocyte 38 cholinesterase activity inhibition in rats and humans are 0.8 and 2.4 hours, respectively, 39 following oral dosing (U.S. EPA 2007b). 40

41 4.2. Mechanism of Toxicity 42
43 Oxamyl is an N -methyl carbamate insecticide/nematicide. The mode of action of 44 carbamate pesticides involves cholinesterase inhibition (Costa 2008). Carbamic acid esters 45 attach to the serine hydroxyl group of the reactive site of acetylcholinesterase, the enzyme 46 responsible for the destruction and termination of the biological activity of the neurotransmitter 47OXAMYL NAC Proposed 1: June 2009/ Page 15 of 36

acetylcholine. When unbound acetylcholine accumulates at the cholinergic nerve endings, there 1 is continual stimulation of electrical activity. The resulting signs of toxicity result from 2 stimulation of the muscarinic receptors of the parasympathetic autonomic nervous system and 3 are manifest as increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, 4 diarrhea, urination, and bradycardia. Stimulation of the parasympathetic junctions of the 5 autonomic nervous system as well as the junctions between nerves and muscles cause 6 tachycardia, hypertension, muscle fasciculation, tr emors, muscle weakness, and flaccid paralysis. 7 Signs resulting from effects on the central nervous system include restlessness, emotional 8 lability, ataxia, lethargy, mental confusion, loss of memory, generalized weakness, convulsions, 9 cyanosis, and coma. Inhibition of acetylcholinesterase activity is transient and reversible 10 because there is rapid reactivation of the carbamylated enzyme in the presence of water. 11

12 Carbamates also inhibit butylcholinesterase, the primary form of cholinesterase found in 13 blood plasma. The toxicological significance of butylcholinesterase activity inhibition is 14 unknown. Acetylcholinesterase is the primary form of cholinesterase found in erythrocytes and 15 is present at neuromuscular and nerve-nerve junctions. A review of studies submitted to U.S. 16 EPA (2007b) for pesticide registration shows that clinical signs and behavioral effects are not 17 evident below 10% acetylcholinesterase activity inhibition. Due to human variability, it is 18
difficult to measure inhibition of <20% from an individual’s baseline (U.S. EPA 2000). At 19 greater than 30% erythrocyte acetylcholinesterase activity inhibition or 50% plasma activity 20 inhibition, workers are withdrawn from pestic ide application areas (U.S. EPA 2000; ACGIH 21 2008). Other enzymes such as carboxylesterases are non-target enzymes to which cholinesterase 22 activity inhibitors may bind. 23

24 4.3. Structure-Activity Relationships 25
26 Organophosphate and carbamate pesticides have a common mode of action (Costa 2008). 27 Compared to organophosphate ester pesticides, the carbamic acid esters are poor substrates for 28 cholinesterase-type enzymes. The carbamic acid esters which attach to the reactive site of acetyl 29 cholinesterase undergo fairly rapid hydrolysis. The carbamylated (inhibited) enzyme is 30 decarbamylated fairly rapidly with generation of the free, active enzyme. 31
32 Information is available on the relative oral toxicity of three carbamate pesticides (HSRB 33 2006; U.S. EPA 2007b). The endpoints were brai n and erythrocyte cholinesterase activity 34 inhibition in the rat and erythrocyte cholinesterase activity inhibition in humans. Raw data on 35 erythrocyte cholinesterase activity inhibition were not provided for all three chemicals, but 36 relative toxicity can be derived from the benchmark doses (BMD 10 and BMDL 10 ) calculated by 37 U.S. EPA (2007b) from a range of oral doses (Tab le 3). For methomyl and oxamyl, rat data on 38 brain and erythrocyte cholinesterase activity are presented by McDaniel et al. (2007). If oxamyl 39 is assigned a relative oral potency factor of 1, th en the oral potencies of aldicarb and methomyl 40 are 4 and 0.67, respectively (U.S. EPA 2007b). 41

42

TABLE 3. Adult Rat and Human BMD 10 and BMDL 10 Values for Cholinesterase Activity Inhibition by N

Methyl Carbamate Pesticides (Oral Dosing)

Rat Human
Brain Erythrocyte Erythrocyte Chemical Benchmark Half-life Benchmark Half-life Benchmark Half-lifeOXAMYL NAC Proposed 1: June 2009/ Page 16 of 36

Dose (mg/kg) (h) Dose (mg/kg) (h) Dose (mg/kg) (h)

Aldicarb BMD 10 : 0.052

BMDL 10 : 0.035 1.5 BMD 10 : 0.031

BMDL 10 : 0.020 1.1 BMD 10 : 0.016

BMDL 10 : 0.013 1.7

Methomyl BMD 10 : 0.486

BMDL 10 : 0.331 1.0 BMD 10 : 0.204

BMDL 10 : 0.112 0.8 BMD 10 : 0.040

BMDL 10 : 0.028 1.6

Oxamyl BMD 10 : 0.165

BMDL 10 : 0.127 0.9 BMD 10 : 0.278

BMDL 10 : 0.158 0.8 BMD 10 : 0.083

BMDL 10 : 0.068 2.4

Benchmark dose data for brain cholinesterase data for aldi carb and oxamyl are presented as the average of male and 1

female rat values. 2

The BMDL 10 for 10% brain cholinesterase activity inhibition wa s used as the point of departure for U.S. EPA 3 (2007b) risk assessment. 4 Source: Table 1.B-9, p. 50, U.S. EPA 2007b. 5 6
4.4. Other Relevant Information 7 4.4.1. Species Variability 8
9 The extent of hydrolysis of carbamate ester insecticides varies among species, ranging 10 from 30 to 95%, and is chemical specific (Costa 2008). Baseline erythrocyte 11 acetylcholinesterase activity is higher in humans than in other species (Ellin 1981). 12
13 Inhalation studies were conducted only with ra ts. Subchronic and chronic feeding studies 14 with the rat, mouse, and dog showed little difference in toxicity among the species. Based on 15 differences in modeled values for erythrocyte acetylcholinesterase activity inhibition between 16 rats and humans, the U.S. EPA Office of Pesticide Programs calculated an oxamyl-specific 17 inhalation interspecies uncertainty factor of 3 (U.S. EPA 2007b). Half-lives for enzyme 18 regeneration of erythrocyte cholinesterase activity were 0.8 hours (adult rats) and 2.4 hours 19 (humans). 20

21 4.4.2. Susceptible Populations 22
23 Humans vary by gender, age, and genetic make-up in sensitivity to cholinesterase 24 inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 activity units; 25 acetylthiocholine substrate) is greater than that of healthy newborn infants (97±15 activity units) 26 by a factor of 1.6 (Herz et al. 1975). Devel opmental neurotoxicity studies showed that 27 protection of the rat dam against cholinesterase activity inhibition is protective against pup 28 acetylcholinesterase activity inhibition in utero . The U.S. EPA (2007b) identified infants and 29 juveniles as the most sensitive population to the anticholinesterase effects of N -methyl carbamate 30 pesticides. In so doing, they evaluated the relative sensitivity of juvenile and adult rats to N

31 methyl carbamate pesticides including oxamyl. Based on comparative brain acetylcholinesterase 32 activity inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated a 33 Food Quality Protection Act (FQPA) uncertainty factor of 3.48 for children. This uncertainty 34 factor corresponds to an AEGL intraspecies uncertainty factor. 35
36 4.4.3. Concentration-Exposure Duration Relationship 37
38 The concentration-time relationship for a single endpoint for many irritant and 39 systemically acting inhalational toxicants may be described by C n x t = k (ten Berge et al. 1986). 40 Data for time-scaling from three studies (DuPont 1969a; DuPont 1969b; Kelly 2001) and two 41OXAMYL NAC Proposed 1: June 2009/ Page 17 of 36

exposure durations (1 and 4 hours) provided consistent results. The least squares derived line 1 describing the slope between the 1 and 4-hour values has an n value of 1.6 (Appendix A). 2
3 4.4.4. Concurrent Exposure Issues 4

5 No information relevant to concurrent exposure issues was located. Dermal absorption 6 may occur, but toxicity is low compared to inhalation exposure as indicated by a dermal LD 50 in 7 rabbits of >2000 mg/kg body weight (IPCS 2002). 8
9
5. DATA ANALYSIS FOR AEGL-1 10 5.1. Summary of Human Data Relevant to AEGL-1 11

12 No human inhalation studies were located in the available literature. No occupational 13 monitoring data were presented by U.S. EPA (2007a). 14
15 5.2. Summary of Animal Data Relevant to AEGL-1 16
17 One study with oxamyl dust was available. In that study, groups of 10 rats/sex inhaled 18 4.9 or 24 mg/m 3 of oxamyl dust for 4 hours (O’Neil 2000; U.S. EPA 2000). Plasma, erythrocyte, 19 and brain cholinesterase activity were inhibited at both concentrations. For the sexes combined, 20 brain cholinesterase activity inhibition averaged 12% and erythrocyte acetylcholinesterase 21 activity inhibition averaged 28.5% at the lower concentration. Respective values were 67.5% 22 and 72.5% at the higher concentration. 23

24
5.3. Derivation of AEGL-1 25
26 The key study for AEGL-1 determination was O’Neil (2000; U.S. EPA 2000). Inhalation 27 of 4.9 mg/m 3 oxamyl dust for 4 hours inhibited erythrocyte acetylcholinesterase activity by 28 28.5% (average of values in males and females) and brain cholinesterase by 12% (average of 29 values in males and females). Erythrocyte acetylcholinesterase activity inhibition of that 30 magnitude may result in transient symptoms of discomfort in humans. Wet stains, ocular/nose 31 discharge and diarrhea were seen in rats exposed to 4.9 and 24 mg/m 3 as well as in the control 32 groups. Additionally tremors and lethargy were seen in the exposed groups, but incidences in 33 the 4.9 mg/m 3 group were reported as similar to those of the control groups (incidence data not 34 reported). U.S. EPA (2007b) derived an interspeci es uncertainty factor of 3 for oxamyl based on 35 differences in modeled values for erythrocyte acetylcholinesterase activity inhibition between 36 rats and humans (See section 4.4.1). Based on comparative brain cholinesterase activity 37 inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated an 38 intraspecies uncertainty factor of 3.48 to protect sensitive young (See section 4.4.2). The 39 combined uncertainty factor is 10.4 (rounded to 10). Female rats were not more sensitive to 40 oxamyl exposure than male rats in this study. Values were time-scaled (C n x t = k) from the 4- 41 hour data point using an n value of 1.6. Values are summarized in Table 4. Calculations are in 42 Appendix B, and a category graph of the toxicity da ta in relation to AEGL values is in Appendix 43

D. 44
45

TABLE 4. AEGL-1 Values for OxamylOXAMYL NAC Proposed 1: June 2009/ Page 18 of 36

10-min 30-min 1-h 4-h 8-hour 3.6 mg/m 3 1.8 mg/m 3 1.2 mg/m 3 0.49 mg/m 3 0.32 mg/m 3

1
6. DATA ANALYSIS FOR AEGL-2 2 6.1. Summary of Human Data Relevant to AEGL-2 3

4
No human inhalation studies were located in the available literature. 5
6 6.2. Summary of Animal Data Relevant to AEGL-2 7
8 No animal studies relevant to deriving AEGL-2 values were located in the available 9 literature. All studies reviewed in Section 3.1 involved mortality. 10

11
6.3. Derivation of AEGL-2 12
13 No data on an oxamyl dust concentration that would result in effects consistent with the 14 definition of an AEGL-2 were available in the open literature. Therefore, AEGL-2 values were 15 derived by dividing the AEGL-3 values by 3. This approach is justified when there is a steep 16 concentration-response curve (NRC 2001). As shown by the study of Kelly (2001) mortality 17 went from 0% at 50 mg/m 3 to 100% when concentration was increased 2.4-fold (120 mg/m 3 ). 18 AEGL-2 values are summarized in Table 5. Calculations are in Appendix B and a category 19 graph of the toxicity data in relation to AEGL values is in Appendix D. 20

21

TABLE 5. AEGL-2 Values for Oxamyl

10-min 30-min 1-h 4-h 8-h 5.3 mg/m 3 2.7 mg/m 3 1.8 mg/m 3 0.73 mg/m 3 0.47 mg/m 3

22
23
7. DATA ANALYSIS FOR AEGL-3 24 7.1. Summary of Human Data Relevant to AEGL-3 25
26 No human inhalation studies relevant to development of AEGL-3 values were located in 27
the available literature. 28
29 7.2. Summary of Animal Data Relevant to AEGL-3 30
31 Because of its low vapor pressure, concentrations of oxamyl vapor high enough to induce 32 mortality could not be attained. Three studies with oxamyl dust addressed lethality in the rat. In 33 a 1-hour study LC 50 values for male and female rats were 170 and 120 mg/m 3 , respectively 34 (DuPont 1969a). The 4-hour LC 50 in male and female rats combined was 64 mg/m 3 (DuPont 35 1969b). A more recent study with rats reported a similar 4-hour LC 50 value, 56 mg/m 3 (Kelly 36 2001). 37
38
7.3. Derivation of AEGL-3 39
40 Studies with oxamyl dust were chosen for development of AEGL values. The more 41 recent, GLP study of Kelly (2001) was chosen as the basis for development of AEGL-3 values. 42OXAMYL NAC Proposed 1: June 2009/ Page 19 of 36

The calculated 1-hour BMCL 05 for lethality is 22 mg/m 3 and the BMC 01 is 33 mg/m 3 (Appendix 1 C). The NAC/AEGL Committee generally uses the BMCL 05 as the estimate at which lethality is 2 not likely to be observed (NRC 2001). U.S. EPA (2007b) derived an interspecies uncertainty 3 factor of 3 for oxamyl based on differences in values for erythrocyte acetylcholinesterase activity 4 inhibition between rats and humans (See section 4.4.1). Based on comparative brain 5 cholinesterase activity inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA 6 calculated an uncertainty factor of 3.48 to protect sensitive young (See section 4.4.2). The 7 combined uncertainty factor is 10.4 (rounded to 10) Although female rats appear to be slightly 8 more sensitive to the toxic effects of oxamyl than male rats, the combined data with application 9 of an uncertainty factor that protects sensitive juveniles provides a reasonable estimate of 10 lethality. Values were time-scaled (C n x t = k) from the 4-hour data point using an n value of 11 1.6. Values are summarized in Table 6, calculations are in Appendix B, and a category graph of 12 the toxicity data in relation to AEGL values is in Appendix D. 13 14

TABLE 6. AEGL-3 Values for Oxamyl

10-min 30-min 1-h 4-h 8-h 16 mg/m 3 8.2 mg/m 3 5.3 mg/m 3 2.2 mg/m 3 1.4 mg/m 3

15
The 4-hour LC 50 for rats in the key study (Kelly 2001) is 56 mg/m 3 . A similar 4-hour 16
LC 50 value (64 mg/m 3 ) for rats was identified in a study conducted 30 years earlier in the same 17 laboratory (DuPont 1969b). 18
19
8. SUMMARY OF AEGLs 20 8.1. AEGL Values and Toxicity Endpoints 21

22 AEGL values are summarized in Table 7. Derivations are summarized in Appendix E. 23

24

TABLE 7. Summary of AEGL Values
Exposure Duration Classification 10-min 30-min 1-h 4-h 8-h

AEGL-1 (Nondisabling) 3.6 mg/m 3 1.8 mg/m 3 1.2 mg/m 3 0.49 mg/m 3 0.32 mg/m 3

AEGL-2 (Disabling) 5.3 mg/m 3 2.7 mg/m 3 1.8 mg/m 3 0.73 mg/m 3 0.47 mg/m 3

AEGL-3 (Lethal) 16 mg/m 3 8.2 mg/m 3 5.3 mg/m 3 2.2 mg/m 3 1.4 mg/m 3

25
26 8.2. Comparison with Other Standards and Guidelines 27
28 Other than AEGLs, no inhalation standards or guidelines for oxamyl have been established 29 (Table 8). For acetylcholinesterase inhibiting chem icals in general, the American Conference of 30 Governmental Industrial Hygienists has established a Biological Exposure Index based on 31 erythrocyte cholinesterase activity (ACGIH 2008). Individuals should leave the area when their 32 erythrocyte acetylcholinesterase activity falls to 70% of their baseline. 33
34OXAMYL NAC Proposed 1: June 2009/ Page 20 of 36

The U.S. EPA (2007b) calculated inhalation BMD 10 values of 5 and 2 mg/m 3 for brain and 1 erythrocyte cholinesterase inhibition, respectively, in humans. The endpoint was a 10% 2 inhibition of erythrocyte cholinesterase activity. 3

4

TABLE 8. Standards and Guidelines for Oxamyl
Exposure Duration Guideline 10 min 30 min 1 h 4 h 8 h
AEGL-1 3.6 mg/m 3 1.8 mg/m 3 1.2 mg/m 3 0.49 mg/m 3 0.32 mg/m 3
AEGL-2 5.3 mg/m 3 2.7 mg/m 3 1.8 mg/m 3 0.73 mg/m 3 0.47 mg/m 3
AEGL-3 16 mg/m 3 8.2 mg/m 3 5.3 mg/m 3 2.2 mg/m 3 1.4 mg/m 3
ERPG-1 (AIHA) a

─ ERPG-2 (AIHA)

─ ERPG-3 (AIHA)

─ IDLH (NIOSH) b ─

REL-TWA (NIOSH) c ─

OSHA PEL (NIOSH) d ─

TLV-TWA (ACGIH) e ─

MAK (Germany) f

─ MAC (The Netherlands) g ─

5 6

a ERPG (Emergency Response Planning Guide lines, American Industrial Hygiene Association 7

The ERPG-1 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 8 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 9 perceiving a clearly defined objectionable odor. 10

The ERPG-2 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 11 exposed for up to one hour without experiencing or devel oping irreversible or other serious health effects or 12 symptoms that could impair an individual = s ability to take protective action. 13

The ERPG-3 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 14 exposed for up to one hour without experiencing or developing life-threatening health effects. 15 16

b IDLH (Immediately Dangerous to Life and Health, Nati onal Institute of Occupational Safety and Health) 17 represents the maximum concentration from which one could escape within 30 minutes without any escape18 impairing symptoms, or any irreversible health effects. 19 20

c NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 21 Time Weighted Average) is defined analogous to the ACGIH-TLV-TWA. 22 23

d OSHA PEL-TWA (Occupational Safety and Health Ad ministration, Permissible Exposure Limits - Time 24 Weighted Average) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 25 hours/day, 40 hours/week. 26 27

e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 28 Time Weighted Average) is the time-weighted average concentra tion for a normal 8-hour workday and a 40-hour 29 workweek, to which nearly all workers may be repeat edly exposed, day after day, without adverse effect. 30 31

f MAK (Maximale Arbeitsplatzkonzentrat ion [Maximum Workplace Concentration]) (Deutsche 32 Forschungsgemeinschaft [German Research Associa tion] is defined analogous to the ACGIH-TLV-TWA. 33 34OXAMYL NAC Proposed 1: June 2009/ Page 21 of 36

g MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 1 auspices of the Ministry of Social Affairs and Employmen t], The Hague, The Netherlands) is defined similar to the 2

ACGIH TLV. 3
4 8.3. Data Adequacy and Research Needs 5
6 Oxamyl has a low vapor pressure and no suitable inhalation exposure studies with 7 humans were located in the available literature. An oral dosing study with human volunteers 8 addressed effects consistent with cholinesterase activity inhibition. Inhalation studies with rats 9 as the test species and involving two time points and dust and aerosol delivery were sufficient for 10
derivation of three AEGL levels for five tim epoints. Studies involving comparisons of 11 cholinesterase activity inhibition between juvenile and adult rats and between rats and humans 12 addressed chemical-specific uncertainty factors. Metabolism pathways and mode of action are 13
well understood. 14
15
9. REFERENCES 16
17 ACGIH (American Conference of Government and Indus trial Hygienists). 2008. TLVs and BEIs Based 18
on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & 19 Biological Exposure Indices. Cincinnati, OH: ACGIH. 20
21 Chang, K.M., and C.O. Knowles. 1979. Metabolism of oxamyl in mice and two-spotted spider mites. 22
Arch. Environ. Contam. Toxicol. 8:499-508. 23
24 Costa, L.G. 2008. Chapter 22: Toxic Effects of Pes ticides. In Casarett & Doull’s Toxicology, The Basic 25
Science of Poisons. 7 th Ed. New York: McGraw-Hill. 26
27 DuPont. 1969a. One-Hour Inhalation Toxicity, Haskell Laboratory Report No. 281-69. Haskell 28 Laboratory for Toxicology and Industrial Me dicine, Newark, DE. (Same as Tayfun 1969b). 29
30 DuPont. 1969b. Acute Dust Inhalation Toxicity. Haskell Laboratory Report No. 280-69. Haskell 31 Laboratory for Toxicology and Industrial Me dicine, Newark, DE. (Same as Tayfun 1969a). 32
33 Ellin, R.I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorus 34 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 35 Biomedical Laboratory Report No. USABML-SP-81-003. Available from the Defense Technical 36 Information Center, AD A1013364. 37
38 Harvey, J., Jr., and J. C-Y. Han. 1978. Metabolism of oxamyl and selective metabolites in the rat. J. 39 Agric. Food Chem. 26:902-910. 40
41 Herz, F., E. Kaplan, and E.S. Scheye. 1975. A long itudinal study of red cell enzymes in infants of low 42 birth weight. Z. Kinderheilk. 120: 217-221. 43
44 HSDB (Hazardous Substances Data Bank). 2004. Oxamyl. Available online: 45 http://toxnet/nlm.nih.gov/cgi-bin/sis/download.txt

. 46
47 HSRB (Human Studies Review Board). 2006. Report of the Human Studies Review Board April 4-6, 48 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 49 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting50 materials/apr-4-6-2006-public-meeti ng/april2006mtgfinalreport62606.pdf. 51OXAMYL NAC Proposed 1: June 2009/ Page 22 of 36

1 IPCS (International Program on Chemical Safety). 1983. Data Sheets on Pesticides No. 54: Oxamyl. 2 World Health Organization. Available online: 3 http://www.inchem.org/documents/pds/pds/pest54_e.htm

. 4
5 IPCS (International Program on Chemical Safety). 2002. Pesticide residues in food – 2002- Joint 6 FAO/WHO Meeting on Pesticide Residues; Oxamyl. World Health Organization. Available online: 7 http://www.inchem.org/documents/jmpr/jmpmono/2002pr11.htm

. 8
9 Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical ( 98%w/w): Inhalation Median Lethal Concentration 10 (LC 50 ) Study in Rats. E.I. du Pont de Nemours and Co., Haskell Laboratory for Toxicology and 11 Industrial Medicine, Newark, DE; La boratory Project ID: DuPont-6331. 12
13 Kennedy, G.L., Jr. 1986a. Acute toxicity studies with oxamyl. Fundam. Appl. Toxicol. 6:423-429. 14
15 Kennedy, G.L., Jr. 1986b. Chronic toxicity, reproductiv e, and teratogenic studies with oxamyl. Fundam. 16 Appl. Toxicol. 7:106-118. 17
18 McDaniel, K.L., S. Padilla, R.S. Marshall, P.M. Ph illips, L. Podhorniak, Y. Qian, and V.C. Moser. 2007. 19 Comparison of acute neurobehavioral and cholinest erase inhibitory effects of N-methylcarbamates in 20
rat. Toxicol. Sci. 98:552-560. 21
22 McFarlane, P. and S. Freestone. 1999. A randomized double blind ascending oral dose study with 23 oxamyl. Inveresk Clinical Research, Riccarton, Edinburgh, Scotland. Laboratory Project ID: HLO24 1998-01505, August 10, 1999. Reviewed in U.S. EPA 2005. 25
26 NRC (National Research Council). 2001. Standi ng Operating Procedures for Developing Acute 27 Exposure Guideline Levels for Hazardous Chemical s. Washington, DC: National Academy Press. 28
29 O’Neil, A.J. 2000. Cholinesterase Inhibition Determin ed in Rats Exposed to Inhalation Atmospheres of 30 Oxamyl Technical (96.9%). Haskell Laboratory of Toxicology and Industrial Medicine, E.I. du Pont 31 de Nemours Co. DuPont Study No. 4383. (Reviewed in U.S. EPA 2000, MRID 45155801). 32
33 O’Neil, M.J., A. Smith, and P.E. Heckelman. 2001. Oxamyl. The Merck Index. Whitehouse Station, 34 NJ: Merck & Co., Inc., p. 6994. 35
36 Padilla, S., R.S. Marshall, D.L. Hunter, and A. Low it. 2007. Time course of cholinesterase inhibition in 37 adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, or 38 propoxur. Toxicol. Appl. Pharmacol. 219:202-209. 39
40 RTECS (Registry of Toxic Effects of Chemical Subs tances). 2008. Canadian Centre for Occupational 41 Health and Safety, MDL Information Systems, Inc.. Available online: http://www.ccohs.ca/

. 42
43 Tayfun, F.O. 1969a. Acute dust inhalation toxicity (ChR-CD rats – head only- four hours). Unpublished 44 DuPont Haskell Laboratory Report HLR 280-69). E.I. duPont de Nemours & Co., Wilmington, DE. 45
46 Tayfun, F.O. 1969b. One-hour inhalation toxicity (ChR-CD rats – head only). Unpublished DuPont 47 Haskell Laboratory Report HLR 281-69). E.I. duPont de Nemours & Co., Wilmington, DE. 48
49 ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response 50 relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13: 301-309. 51
52OXAMYL NAC Proposed 1: June 2009/ Page 23 of 36

U.S. EPA (U.S. Environmental Protection Agency). 1997. Initial Submission: Letter from [name 1 deleted] to USEPA Reporting Results of Acute I nhalation Study of Oxamyl in Rats, Dated 5/23/1997 2 (Sanitized). OTS0559122, available from National Technical Information Service, Springfield, VA. 3
4 U.S. EPA (U.S. Environmental Protection Agency). 1998. Data Evaluation Record: Oxamyl (MRID 5 44504901). Available online: Regulations.gov/oxamy l 103801. Citation: E.I. duPont de Nemours 6 and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, Newark, 7 DE. Laboratory Project ID: HL-1998-00708, February 23, 1998. 8
9 U.S. EPA (U.S. Environmental Protection Agency). 2000. Data Evaluation Record: Oxamyl (MRID 10 45155801). Citation: O’Neil, A.J. 2000. Cholinester ase inhibition determined in rats exposed to 11 inhalation atmospheres of oxamyl technical (96. 9%). Haskell Laboratory of Toxicology and 12 Industrial Medicine, E.I. du Pont de Nemours Co. DuPont Study No. 4383. 13
14 U.S. EPA (U.S. Environmental Protection Agency). 2005. Data Evaluation Record: Oxamyl/103801 15 (MRID 44912301). Available online: Regulations.gov/ oxamyl 103801. Citation: McFarlane, P. and 16 S. Freestone. 1999. A randomized double blind ascending oral dose study with oxamyl. Inveresk 17 Clinical Research, Riccarton, Edinburgh, Scotland. Laboratory Project ID: HLO-1998-01505, 18 August 10, 1999. 19
20 U.S. EPA (U.S. Environmental Protection Agency). 2007a. Reregistration Eligibility Decision (RED) 21 for Oxamyl. Available online: www.epa.gov/pesticides/reregistration/REDs/oxamyl_red.pdf

. 22
23 U.S. EPA (U.S. Environmental Protection Agency). 2007b. Revised N -Methyl Carbamate Cumulative 24 Risk Assessment. Office of Pesticide Programs. Available online: 25 http://www.epa.gov/oppsrrd1/REDs/nmc_revised_cra.pdf

. 26
27
28OXAMYL NAC Proposed 1: June 2009/ Page 24 of 36

1 APPENDIX A: Time-Scaling Calculation for Oxamyl AEGLs 2
3

1.7 1.8 1.9

2 2.1 2.2 2.3Log Concentration (ppm)

1.7 1.8 1.9 2 2.1 2.2 2.3 2.4 Log Time (minutes) Best Fit Concentration x Time Curve

4 5 Time scaling of LC 50 values was based on the 1-hour study of DuPont 1969a and the 4-hour studies of 6 DuPont 1969b and Kelly 2001. 7
8

Time (minutes) Concentration Log Time Log
Concentration 60 170 1.7782 2.2304 Regression Output: 60 120 1.7782 2.0792 Intercept 3.2701 240 64 2.3802 1.8062 Slope -0.6272 240 56 2.3802 1.7482 R Squared 0.9157

Correlation -0.9569 Degrees of Freedom 2

Observations 4

n = 1.59 9

k = 163526.7 10
11OXAMYL NAC Proposed 1: June 2009/ Page 25 of 36

1 APPENDIX B: Derivation of Oxamyl AEGLs 2
3
Derivation of AEGL-1 Values 4
5 Key Study: O’Neil, A.J. 2000. Cholinesterase Inhibition determined in Rats Exposed to 6 Inhalation Atmospheres of Oxamyl Technical (96.9%). Haskell Laboratory 7 of Toxicology and Industrial Medicine, E.I. du Pont de Nemours Co. DuPont 8 Study No. 4383. (Summarized in U.S. EPA 2000). 9
10 Toxicity endpoint: Clinical signs of ocular/nasal discharge, diarrhea, tremors, and lethargy (the 11 latter two signs also seen in control ra ts) following a 4-hour exposure of rats 12 to 4.9 mg/m 3 . For the sexes combined, brain cholinesterase activity 13 inhibition averaged 12% and erythrocyte acetylcholinesterase activity 14 inhibition averaged 28.5%. 15
16 Time scaling C n x t = k where n = 1.6 based on time scaling from the 1- and 4-hour rat data 17 (three studies) with oxamyl dust. 18
19 Uncertainty factors: Total uncertainty factor: 10 20 Interspecies: 3 – The U.S. EPA (2007b) Office of Pesticide Programs 21 calculated an oxamyl-specific inhalation interspecies uncertainty 22 factor of 3 based on differences in values for erythrocyte 23 acetylcholinesterase activity inhibition between rats and humans. 24 Intraspecies: 3.48 – The U.S. EPA (2007b) Office of Pesticide 25 Programs calculated an oxamyl-specific inhalation intraspecies 26 uncertainty factor of 3.48 based on comparative brain 27 acetylcholinesterase activity inhibition in post-natal day 11 juvenile 28
rats and adult rats. 29
30 Modifying factor: None applied 31
32 Calculations: (4.9 mg/m 3 /10) 1.6 x 240 minutes = 76.65 mg/m 3(1.6) •min 33
34
10-min AEGL-1: C = 1.6 √ (76.65 mg/m 3(1.6) •min/10) = 3.6 mg/m 3 35
36
30-min AEGL-1: C = 1.6 √ (76.65 mg/m 3(1.6) •min/30) = 1.8 mg/m 3 37
38
1-h AEGL-1: C = 1.6 √ (76.65 mg/m 3(1.6) •min/60) = 1.2 mg/m 3 39
40 4-h AEGL-1: C = 4.9 mg/m 3 /10 = 0.49 mg/m 3 41
42
8-h AEGL-1: C = 1.6 √ (76.65 mg/m 3(1.6) •min/480) = 0.32 mg/m 3 43
44
45OXAMYL NAC Proposed 1: June 2009/ Page 26 of 36

1
Derivation of AEGL-2 Values 2
3 Key Study: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation 4 Median Lethal Concentration (LC 50 ) Study in Rats. E.I. du Pont de Nemours 5 and Co., Haskell Laboratory for Toxi cology and Industrial Medicine, 6 Newark, DE; Laboratory Project ID: DuPont-6331. 7 8 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentration-response line shown 9 by the Kelly (2001) data justifies deriving AEGL-2 values by dividing the 10 AEGL-3 values by 3 (NRC 2001). 11
12 Time scaling C n x t = k where n = 1.6 based on time scaling from the 1- and 4-hour rat data 13 (three studies) with oxamyl dust. 14
15 Uncertainty factors: Total uncertainty factor: 10 (See AEGL-3 below) 16
17
Calculations: AEGL-3 values/3 18
19 10-min AEGL-2: C = 16/3 = 5.3 mg/m 3 20
21 30-min AEGL-2: C = 8.2/3 = 2.7 mg/m 3 22
23 1-h AEGL-2: C = 5.3/3 = 1.8 mg/m 3 24
25 4-h AEGL-2: C = 2.2/3 = 0.73 mg/m 3 26
27 8-h AEGL-2: C = 1.4/3 = 0.47 mg/m 3 28
29OXAMYL NAC Proposed 1: June 2009/ Page 27 of 36

1
Derivation of AEGL-3 Values 2
3 Key Study: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation 4 Median Lethal Concentration (LC 50 ) Study in Rats. E.I. du Pont de Nemours 5 and Co., Haskell Laboratory for Toxi cology and Industrial Medicine, 6 Newark, DE; Laboratory Project ID: DuPont-6331. 7 8 Toxicity endpoint: Threshold for lethality in rats at the BMCL 05 of 22.2692 mg/m 3 calculated 9 from the rat lethality data of Kelly (2001). 10
11 Time scaling C n x t = k where n = 1.6 based on time scaling from the 1- and 4-hour rat data 12 (three studies) with oxamyl dust. 13
14 Uncertainty factors: Total uncertainty factor: 10 15 Interspecies: 3 – The U.S. EPA Office of Pesticide Programs (2007b) 16 calculated an oxamyl-specific inhalation interspecies uncertainty 17 factor of 3 based on differences in values for erythrocyte 18 cholinesterase activity inhibition between rats and humans. 19 Intraspecies: 3.48 – The U.S. EPA Office of Pesticide Programs 20 (2007b) calculated an oxamyl-specific inhalation intraspecies 21 uncertainty factor of 3.48 based on comparative brain 22 acetylcholinesterase activity inhibition in post-natal day 11 juvenile 23
rats and adult rats. 24
25 Modifying factor: None applied 26
27 Calculations: (22.27 mg/m 3 /10)1.6 x 240 minutes = 864.05 mg/m 3(1.6) •min 28
29
10-min AEGL-3: C = 1.6 √ (864.05 mg/m 3(1.6) •min/10) = 16 mg/m 3 30
31
30-min AEGL-3: C = 1.6 √ (864.05 mg/m 3(1.6) •min/30) = 8.2 mg/m 3 32
33
1-h AEGL-3: C = 1.6 √ (864.05 mg/m 3(1.6) •min/60) = 5.3 mg/m 3 34
35 4-h AEGL-3: C = 22.27/10 = 2.2 mg/m 3 36
37
8-h AEGL-3: C = 1.6 √ (864.05 mg/m 3(1.6) •min/480) = 1.4 mg/m 3 38
39
40OXAMYL NAC Proposed 1: June 2009/ Page 28 of 36

APPENDIX C: Benchmark Concentr ation Calculations for Oxamyl 1

2
Calculation of BMC 01 : Data of Kelly 2001 3

============================================================== 4 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 5 Input Data File: C:\BMDS\OXAMYL _RAT.(d) 6 Gnuplot Plotting File: C:\BMDS\OXAMYL _RAT.plt 7
Wed Feb 25 13:36:33 2009 8

============================================================== 9
10

BMDS MODEL RUN 11

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 12
13 The form of the probability function is: 14
15 P[response] = Background + (1-Backgr ound) * CumNorm(Intercept+Slope*Log(Dose)), 16
17 where CumNorm(.) is the cumulative normal distribution function 18
19 Dependent variable = COLUMN3 20 Independent variable = COLUMN1 21 Slope parameter is not restricted 22
23
Total number of observations = 5 24 Total number of records with missing values = 0 25
Maximum number of iterations = 250 26 Relative Function Convergence has been set to: 1e-008 27 Parameter Convergence has been set to: 1e-008 28
29 User has chosen the log transformed model 30
31 Default Initial (and Specified) Parameter Values 32 background = 0 33 intercept = -9.7974 34 slope = 2.42048 35
36 Asymptotic Correlation Matrix of Parameter Estimates 37
38 ( *** The model parameter(s) -background 39 have been estimated at a boundary point, or have been specified by the user, 40 and do not appear in the correlation matrix ) 41
42 intercept slope 43 intercept 1 -1 44 slope -1 1 45
Parameter Estimates 46
Variable Estimate Std. Err. 47 background 0 NA 48 intercept -17.86 8.42225 49 slope 4.43819 2.09164 50
51 NA - Indicates that this parameter has hit a bound implie d by some inequality constraint and thus has no 52OXAMYL NAC Proposed 1: June 2009/ Page 29 of 36

standard error. 1
2 Analysis of Deviance Table 3 Model Log(likelihood) Deviance Test DF P-value 4
Full model -17.8428 5
Fitted model -18.7358 1.78596 3 0.618 6
Reduced model -34.6574 33.6292 4 <.0001 7 8

AIC: 41.4715 9
10
Goodness of Fit Scaled 11 Dose Est._Prob. Expected Observed Size Residual 12

------------------------------------------------------------------------ 13

0.0000 0.0000 0.000 0 10 0 14

50.0000 0.3093 3.093 2 10 -0.748 15

54.0000 0.4379 4.379 6 10 1.033 16

65.0000 0.7475 7.475 7 10 -0.3458 17

120.0000 0.9996 9.996 10 10 0.05937 18
19 Chi-square = 1.75 DF = 3 P-value = 0.6260 20
21 Benchmark Dose Computation 22
23 Specified effect = 0.01 24 Risk Type = Extra risk 25
Confidence level = 0.95 26
27

BMC 01 = 33.1158 28
29

BMCL 01 = 15.6441 30
31

0 0.2 0.4 0.6 0.8

1

0 20 40 60 80 100 120Fraction Affected

dose Probit Model with 0.95 Confidence Level

13:36 02/25 2009 BMDL BMD Probit

32OXAMYL NAC Proposed 1: June 2009/ Page 30 of 36

Calculation of BMCL 05 : Data of Kelly 2001 1

============================================================== 2 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 3 Input Data File: C:\BMDS\OXAMYL _RAT.(d) 4 Gnuplot Plotting File: C:\BMDS\OXAMYL _RAT.plt 5
Wed Feb 25 13:36:33 2009 6

============================================================== 7

BMDS MODEL RUN 8

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9 The form of the probability function is: P[response] = Background + (1-Background) * CumNorm 10 (Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function 11
12 Dependent variable = COLUMN3 13 Independent variable = COLUMN1 14 Slope parameter is not restricted 15
16
Total number of observations = 5 17 Total number of records with missing values = 0 18
Maximum number of iterations = 250 19 Relative Function Convergence has been set to: 1e-008 20 Parameter Convergence has been set to: 1e-008 21
22 User has chosen the log transformed model 23
24 Default Initial (and Specified) Parameter Values 25 background = 0 26 intercept = -9.7974 27 slope = 2.42048 28
29 Asymptotic Correlation Matrix of Parameter Estimates 30
31 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been 32 specified by the user, and do not appear in the correlation matrix ) 33
34 intercept slope 35
36 intercept 1 -1 37
38 slope -1 1 39
40
Parameter Estimates 41
42
Variable Estimate Std. Err. 43 background 0 NA 44 intercept -17.86 8.42225 45 slope 4.43819 2.09164 46
47 NA - Indicates that this parameter has hit a bound implie d by some inequality constraint and thus has no 48
standard error. 49
50 Analysis of Deviance Table 51
52OXAMYL NAC Proposed 1: June 2009/ Page 31 of 36

Model Log(likelihood) Deviance Test DF P-value 1
Full model -17.8428 2
Fitted model -18.7358 1.78596 3 0.618 3
Reduced model -34.6574 33.6292 4 <.0001 4
5

AIC: 41.4715 6
7
Goodness of Fit 8
Scaled 9 Dose Est._Prob. Expected Observed Size Residual 10

------------------------------------------------------------------------ 11

0.0000 0.0000 0.000 0 10 0 12

50.0000 0.3093 3.093 2 10 -0.748 13

54.0000 0.4379 4.379 6 10 1.033 14

65.0000 0.7475 7.475 7 10 -0.3458 15

120.0000 0.9996 9.996 10 10 0.05937 16
17 Chi-square = 1.75 DF = 3 P-value = 0.6260 18
19 Benchmark Dose Computation 20
21 Specified effect = 0.05 22 Risk Type = Extra risk 23
Confidence level = 0.95 24
25

BMC 05 = 38.612 26
27

BMCL 05 = 22.2692 28
29

0 0.2 0.4 0.6 0.8

1

0 20 40 60 80 100 120Fraction Affected

dose Probit Model with 0.95 Confidence Level

13:42 02/25 2009 BMDL BMD Probit

30 31OXAMYL NAC Proposed 1: June 2009/ Page 32 of 36



### APPENDIX D: Category Graph of AE GL Values and Toxicity Data 1

2

0 1 10 100 1000mg/m3

0 60 120 180 240 300 360 420 480 Minutes No Effect

Discomfort

Disabling

Some Lethality

Lethal

AEGL Chemical Toxicity - Animal Data Oxamyl

AEGL-3

AEGL-2

AEGL-1

3 4

5
Data : 6
For Category 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species mg/m 3 Minutes Category

NAC/AEGL-1 3.6 10 AEGL

NAC/AEGL-1 1.8 30 AEGL

NAC/AEGL-1 1.2 60 AEGL

NAC/AEGL-1 0.49 240 AEGL

NAC/AEGL-1 0.32 480 AEGL

NAC/AEGL-2 5.3 10 AEGL

NAC/AEGL-2 2.7 30 AEGL

NAC/AEGL-2 1.8 60 AEGL

NAC/AEGL-2 0.73 240 AEGL

NAC/AEGL-2 0.47 480 AEGL

NAC/AEGL-3 16 10 AEGL

NAC/AEGL-3 8.2 30 AEGL

NAC/AEGL-3 5.3 60 AEGL

NAC/AEGL-3 2.2 240 AEGLOXAMYL NAC Proposed 1: June 2009/ Page 33 of 36

NAC/AEGL-3 1.4 480 AEGL

DuPont 1969a rat (male) 140 60 2 (clinical signs – facial fasciculations, salivation, lacrimation dyspnea, etc.) rat (male) 160 60 SL (mortality: 2 of 6) rat (male) 180 60 SL (mortality: 4 of 6) rat (male) 210 60 SL (mortality: 5 of 6)

DuPont 1969a rat (female) 100 60 SL (mortality: 1 of 6) rat (female) 120 60 SL (mortality: 3 of 6) rat (female) 140 60 SL (mortality: 5 of 6)

DuPont 1969b rat (male) 20 240 2 (clinical signs – facial fasciculations, salivation, lacrimation dyspnea, etc.) rat (male) 53 240 SL (mortality: 1 of 6) rat (male) 66 240 SL (mortality: 3 of 6) rat (male) 77 240 SL (mortality: 5 of 6) rat (male) 90 240 3 (mortality: 6 of 6)

Kelly 2001 rat (both sexes) 50 240 SL (mortality: 2 of 10) rat (both sexes) 54 240 SL (mortality: 6 of 10) rat (both sexes) 65 240 SL (mortality: 7 of 10) rat (both sexes) 120 240 3 (mortality: 10 of 10)

1OXAMYL NAC Proposed 1: June 2009/ Page 34 of 36

1 

### APPENDIX E: Derivation Summary for Oxamyl AEGLs 2 Acute Exposure Guideline Levels For Oxamyl 3 (CAS Reg. No. 23135-22-0) 4

5

AEGL-1 VALUES

10-min 30-min 1-h 4-h 8-hour 3.6 mg/m 3 1.8 mg/m 3 1.2 mg/m 3 0.49 mg/m 3 0.32 mg/m 3

Key Reference : O’Neil, A.J. 2000. Cholinesterase Inhibiti on Determined in Rats Exposed to Inhalation Atmospheres of Oxamyl Technical (96.9%). Haskell Laboratory of Toxicology and Industrial Medicine, E.I. du Pont de Nemours Co. DuPont Study No. 4383. Test Species/Strain/Sex/Number : Rat/Crl:CD/male and female/groups of 10 of each sex Exposure Route/Concentration/Duration : Inhalation/4.9 mg/m 3 /4 hours

Effects : Clinical signs of ocular/nose discharge, diarrhea, tremors, lethargy (the latter two signs seen in control rats) Endpoint/Concentration/Rationale : Clinical signs of slight acetylcholinesterase activity inhibition at 4.9 mg/m 3 for 4 hours meet the definition of an AEGL-1. Inhalation of 4.9 mg/m 3 oxamyl dust for 4 hours inhibited erythrocyte acetylcholinesterase activity by 28.5% (ave rage of values in males and females) and brain cholinesterase by 12% (average of values in males and females). Uncertainty Factors/Rationale : Total uncertainty factor : 10

Interspecies: 3, The U.S. EPA (2007b) Office of Pestic ide Programs calculated an oxamyl-specific inhalation interspecies uncertainty factor of 3 base d on comparative erythrocyte cholinesterase activity
inhibition in rats and humans. Intraspecies : 3.48, The U.S. EPA (2007b) Office of Pes ticide Programs calculated an oxamyl-specific inhalation intraspecies uncertainty factor of 3.48 ba sed on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 juvenile rats and adult rats. Modifying Factor : None applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : C n x t = k, where n = 1.6 calculated from three lethality studies Data Adequacy : The key study was well-conducted, used adequa te numbers of rats, and provided analytical
concentrations.
6 7OXAMYL NAC Proposed 1: June 2009/ Page 35 of 36

1

AEGL-2 VALUES

10-min 30-min 1-h 4-h 8-h 5.3 mg/m 3 2.7 mg/m 3 1.8 mg/m 3 0.73 mg/m 3 0.47 mg/m 3

Key Reference : Kelly, D.P. 2001. Oxamyl (DPX-D1410) T echnical (98%w/w): Inhalation Median Lethal Concentration (LC 50 ) Study in Rats. E.I. du Pont de Nemours and Co., Haskell Laboratory for Toxicology and industrial Medicine, Newark , DE; Laboratory Project ID: DuPont-6331. Test Species/Strain/Number : Rat/Crl-CD/groups of 5/sex Exposure Route/Concentration/Duration : 4 hours

Effects : acetylcholinesterase activity inhibition, es timated at 1/3 of the AEGL-3 values. Endpoint/Concentration/Rationale : One-third of the AEGL-3 values , based on the steep concentrationresponse curve (1/3 of the 4-hour BMCL 05 for lethality, 22 mg/m 3 ) Uncertainty Factors/Rationale : Total uncertainty factor : 10 used for derivation of AEGL-3

Interspecies: 3 Intraspecies : 3.48 Modifying Factor : None applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : C n x t = k, where n = 1.6 calculated from three lethality studies Data Adequacy : The key study was well-conducted, used adequa te numbers of rats, and provided analytical concentrations. Values are supported by a second study (DuPont 1969b).
2 3 4OXAMYL NAC Proposed 1: June 2009/ Page 36 of 36

1

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h 16 mg/m 3 8.2 mg/m 3 5.3 mg/m 3 2.2 mg/m 3 1.4 mg/m 3

Key Reference: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Tec hnical (98%w/w): Inhalation Median Lethal Concentration (LC 50 ) Study in Rats. E.I. du Pont de Nemours and Co., Haskell Laboratory for Toxicology and industrial Medicine, Newark , DE; Laboratory Project ID: DuPont-6331. Test Species/Strain/Number : Rat/Crl-CD/groups of 5/sex Exposure Route/Concentration/Duration: 4 hours

Effect : clinical signs consistent with acetylc holinesterase activity inhibition; lethality Endpoint/Concentration/Rationale : 4-hour BMCL 05 , 22 mg/m 3 , threshold for lethality Uncertainty Factors/Rationale : Total uncertainty factor : 10

Interspecies: 3, The U.S. EPA (2007b) Office of Pestic ide Programs calculated an oxamyl-specific inhalation interspecies uncertainty factor of 3 base d on modeled values for erythrocyte cholinesterase activity inhibition between rats and humans. Intraspecies : 3.48, The U.S. EPA (2007b) Office of Pes ticide Programs calculated an oxamyl-specific inhalation intraspecies uncertainty factor of 3.48 ba sed on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 j uvenile rats and adult rats. Modifying Factor : None applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : n value of 1.6 (C n x t = k) calculated from three lethality studies Data Adequacy: The key study was well-conducted, used adequate numbers of rats, and provided analytical concentrations. Values are supported by a second study (DuPont 1969b).

2