1 NAC Proposed 1: June 2009

2 

3 

4 

5 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

6 FOR

7 OXAMYL

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

9 

10 

11 

12 

13 PROPOSED 

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

1 

2 PREFACE

3 

4 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

5 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

6 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

7 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

8 chemicals. 

9 

10 AEGLs represent threshold exposure limits for the general public and are applicable to 

11 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels – AEGL-1, 

12 AEGL-2 and AEGL-3 – are developed for each of five exposure periods (10 and 30 minutes, 1 

13 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

14 The three AEGLs are defined as follows: 

15 

16 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

cubic meter [ppm or mg/m3 17 ]) of a substance above which it is predicted that the general 

18 population, including susceptible individuals, could experience notable discomfort, irritation, or 

19 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

20 transient and reversible upon cessation of exposure. 

21 

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 22 ) of a substance above 

23 which it is predicted that the general population, including susceptible individuals, could 

24 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

25 to escape. 

26 

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 27 ) of a substance above 

28 which it is predicted that the general population, including susceptible individuals, could 

29 experience life-threatening health effects or death. 

30 

31 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

32 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

33 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

34 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 

35 severity of effects described for each corresponding AEGL. Although the AEGL values 

36 represent threshold levels for the general public, including susceptible subpopulations, such as 

37 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 

38 that individuals, subject to unique or idiosyncratic responses, could experience the effects 

39 described at concentrations below the corresponding AEGL. 

40 
OXAMYL NAC Proposed 1: June 2009/ Page 3 of 36 

1 TABLE OF CONTENTS 

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

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

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

5 2. HUMAN TOXICITY DATA...............................................................................................................8 

6 3. ANIMAL TOXICITY DATA..............................................................................................................9 

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

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

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

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

11 3.5. Developmental/Reproductive Toxicity......................................................................................12 

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

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

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

15 4. SPECIAL CONSIDERATIONS ........................................................................................................14 

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

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

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

19 4.4. Other Relevant Information.......................................................................................................16 

20 4.4.1. Species Variability ................................................................................................................16 

21 4.4.2. Susceptible Populations ........................................................................................................16 

22 4.4.3. Concentration-Exposure Duration Relationship ...................................................................16 

23 4.4.4. Concurrent Exposure Issues..................................................................................................17 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8 8.3. Data Adequacy and Research Needs .........................................................................................21 

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

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

11 APPENDIX B: Derivation of Oxamyl AEGLs..........................................................................................25 

12 APPENDIX C: Benchmark Concentration Calculations for Oxamyl........................................................28 

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

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

1 LIST OF TABLES 

2 

3 S 1. Summary of AEGL Values for Oxamyl.....................................................................................................7

4 TABLE 1. Chemical and Physical Properties ..............................................................................................................8

5 TABLE 2. Mortality of Rats Exposed to Oxamyl for 1 or 4 Hours ...........................................................................10

6 TABLE 3. Adult Rat and Human BMD10 and BMDL10 Values for Cholinesterase Activity Inhibition by N-Methyl 

7 Carbamate Pesticides (Oral Dosing) ........................................................................................................15

8 TABLE 4. AEGL-1 Values for Oxamyl ....................................................................................................................17

9 TABLE 5. AEGL-2 Values for Oxamyl ....................................................................................................................18

10 TABLE 6. AEGL-3 Values for Oxamyl ....................................................................................................................19

11 TABLE 7. Summary of AEGL Values ......................................................................................................................19

12 TABLE 8. Standards and Guidelines for Oxamyl......................................................................................................20

13 

14 

15 
OXAMYL NAC Proposed 1: June 2009/ Page 6 of 36 

1 SUMMARY

2 

3 Oxamyl (CAS No. 23135-22-0) is a crystalline solid N-methyl carbamate insecticide with 

4 a slightly sulfurous odor. Oxamyl is used as an insecticide, nematicide, and acaricide on field 

5 crops such as vegetables, fruits, and ornamentals. It is sold as a granule formulation or as a 

6 liquid formulation under the trade name VydateTM. Solid oxamyl is very stable and has a low 

7 vapor pressure. Oxamyl is manufactured commercially by chlorination of the oxime of methyl 

8 glycolate, reaction of that product with methanethiol and alkali, followed by reaction with 

9 dimethylamine, and conversion to the carbamate with methyl isocyanate. Approximately 

10 800,000 pounds of active ingredient are applied annually in the United States. Application to 

11 cotton fields accounts for most of the usage. 

12 

13 Oxamyl and other carbamate pesticides are neurotoxic in that they are inhibitors of the 

14 enzyme acetylcholinesterase. Inhibition of acetylcholinesterase, responsible for termination of 

15 the biological activity of the neurotransmitter acetylcholine at various nerve endings, produces 

16 sustained stimulation of electrical activity. Depending on the concentration administered, signs 

17 following acute exposure of rats to oxamyl may include facial fasciculations, tremors, salivation, 

18 lacrimation, gasping and convulsions. In humans, inhibition of erythrocyte acetylcholinesterase 

19 activity is used as a biomarker of methyl carbamate exposure and effects. No inhalation studies 

20 involving human subjects were located. Given that methyl carbamate pesticides do not have a 

21 port of entry effect, are expected to be rapidly absorbed, and do not require activation, relative 

22 acetylcholinesterase activity inhibition levels measured from oral studies with humans and 

23 juvenile and adult rats were used to derive interspecies and intraspecies uncertainty factors. 

24 

25 The recent well-conducted study of O’Neil (2000, reviewed in U.S. EPA 2000) with rats 

26 inhaling oxamyl dust was chosen as the key study to derive AEGL-1 values. In that study, male 

and female rats inhaled 4.9 mg/m3 27 of oxamyl dust for 4 hours. Erythrocyte acetylcholinesterase 

28 activity was inhibited by an average 28.5% and brain cholinesterase by an average 12% (sexes 

29 combined). Erythrocyte acetylcholinesterase activity inhibition of that magnitude may result in 

transient symptoms of discomfort in humans. Exposure to 24 mg/m3 30 for 4 hours resulted in 

31 average erythrocyte and brain cholinesterase activity inhibition of 67-73%. Following exposure, 

32 rats showed ocular/nose discharge, diarrhea, tremors, and lethargy. Signs were similar in the 

control and 4.9 mg/m3

 exposure groups. The 4-hour 4.9 mg/m3 33 value was divided by inter- and 

34 intraspecies uncertainty factors of 3 and 3.48, respectively, for a total of 10. The chemical35 specific uncertainty factors were calculated by U.S. EPA (2007b). Their oxamyl-specific 

36 interspecies inhalation uncertainty factor was based on differences in modeled values for 

37 erythrocyte cholinesterase activity inhibition between rats and humans following oral dosing. 

38 Based on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 juvenile 

39 rats and adult rats, the U.S. EPA calculated an uncertainty factor of 3.48 to protect sensitive 

young. The resulting 0.49 mg/m3

 value was time-scaled (Cn 40 x t = k) from the 4-hour data point 

41 using an n value of 1.6 derived from three lethality studies involving exposure durations of 1 and 

42 4 hours. 

43 

44 No studies that addressed effects consistent with the definition of the AEGL-2 tier were 

45 found. The concentration-response curve for lethality in rats is steep. As shown by the study of 

Kelly (2001), mortality went from 0% at 50 mg/m3 46 to 100% when concentration was increased 
OXAMYL NAC Proposed 1: June 2009/ Page 7 of 36 

2.4-fold (120 mg/m3 1 ). Therefore, according to Standard Operating Procedures (NRC 2001), the 

2 AEGL-2 values were derived by dividing the AEGL-3 values by 3. 

3 

4 The study of Kelly (2001) with male and female rats was chosen as the basis for 

5 development of AEGL-3 values. The study was conducted according to U.S. EPA guidelines. 

The calculated 4-hour BMCL05 for lethality for oxamyl dust was 22 mg/m3

. The 22 mg/m3 6 value 

7 was divided by inter- and intraspecies uncertainty factors of 3 and 3.48 for a total of 10. U.S. 

8 EPA (2007b) derived an interspecies uncertainty factor of 3 for oxamyl based on differences in 

9 values for erythrocyte acetylcholinesterase activity inhibition between rats and humans. Based 

10 on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 juvenile rats 

11 and adult rats, the U.S. EPA calculated an uncertainty factor of 3.48 to protect sensitive young. 

12 The combined (rounded) uncertainty factor is 10. Although female rats appear to be slightly 

13 more sensitive to the toxic effects of oxamyl than male rats, the combined data with application 

14 of an uncertainty factor that protects sensitive juveniles provides a reasonable estimate of 

lethality. Values were time-scaled (Cn 15 x t = k) from the 4-hour data point using an n value of 

16 1.6. The n value of 1.6 was based on three studies that encompassed exposure durations of one 

17 and four hours. 

18 

19 The calculated values are listed in the table below. 

20 

S 1. Summary of AEGL Values for Oxamyl

Classification 10-min 30-min 1-h 4-h 8-h 

Endpoint 

(Reference) 

AEGLB1 

(Nondisabling) 

3.6 mg/m3 1.8 mg/m3 1.2 mg/m3 0.49 mg/m3 0.32 mg/m3 Slight symptoms of 

cholinesterase activity 

inhibition – rat 

(O’Neil 2000; U.S. 

EPA 2000) 

AEGLB2 

(Disabling) 

5.3 mg/m3 2.7 mg/m3 1.8 mg/m3 0.73 mg/m3 0.47 mg/m3 AEGL-3 values 

divided by 3 based on 

steep concentrationresponse curve 

AEGLB3 

(Lethal) 

16 mg/m3 8.2 mg/m3 5.3 mg/m3 2.2 mg/m3 1.4 mg/m3 4-hour BMCL05 for 

lethality– rat data 

(Kelly 2001) 

21 

22 

23 1. INTRODUCTION

24 

25 Technical oxamyl (CAS No. 23135-22-0) is a crystalline solid N-methyl carbamate 

26 insecticide with a slight sulfurous odor. Oxamyl is used as an insecticide, nematicide, and 

27 acaricide on field crops such as vegetables, fruits, and ornamentals. It is sold under the trade 

28 names VydateTM and Vydate LTM. Technical grade oxamyl contains 89% a.i. (active ingredient). 

29 It is registered for use as liquid formulations (24 and 42% a.i.) and as a technical solid (42% 

30 a.i.). Vydate L is a water soluble liquid containing 24% oxamyl (Kennedy 1986a; HSDB 2004; 

31 U.S. EPA 2007a). Oxamyl is also commercially available as a granule formulation (10% a.i.) 

32 and as technical material in cyclohexanone/water at 42% a.i. Solid oxamyl is very stable (IPCS 

33 1983). The chemical and physical properties of oxamyl are listed in Table 1. 
OXAMYL NAC Proposed 1: June 2009/ Page 8 of 36 

1 

2 Oxamyl is manufactured commercially by chlorination of the oxime of methyl glycolate, 

3 reaction of that product with methanethiol and alkali, followed by reaction with dimethylamine, 

4 and conversion to the carbamate with methyl isocyanate (HSDB 2004). Approximately 800,000 

5 pounds of active ingredient are applied annually in the United States (U.S. EPA 2007a). Cotton 

6 accounts for most of the usage. 

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 C7H13N3O3S 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/cm2 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/m3

1 mg/m3

 = 0.11 ppm 

Calculated 

8 

9 

10 2. HUMAN TOXICITY DATA 

11 

12 No inhalation studies other than accidental exposures were located. These accidental 

13 exposures lacked information on concentration and exposure duration. No occupational 

14 monitoring data were presented by U.S. EPA (2007a). An oral dosing study was conducted by 

15 McFarlane and Freestone (1999; reviewed in U.S. EPA 2005). The Human Studies Review 

16 Board (HSRB 2006) reviewed the study and found it met ethical considerations (required by 

17 EPA’s Human Subjects Protection Rule). Forty healthy male subjects, ages 19-39 years, in 

18 groups of five, ingested a gelatin capsule of oxamyl at doses of 0.005, 0.015, 0.03, 0.06, 0.09, or 

19 0.15 mg a.i./kg body weight. Ten subjects received a placebo capsule. The dose was 

20 accompanied with a light breakfast. Clinical symptoms and signs were recorded pre-dose and at 

21 set times post-dose. Plasma and erythrocyte cholinesterase activity were assayed pre-dose and at 

22 set times post-dose. Clinical signs were reported by three subjects in the placebo group, three 

23 subjects in the 0.015 mg/kg dose group, one subject in the 0.03 mg/kg dose group, and one 
OXAMYL NAC Proposed 1: June 2009/ Page 9 of 36 

1 subject in the 0.15 mg/kg dose group. Incidences of these signs did not show a dose-response 

2 relationship and did not correspond with cholinesterase activity inhibition in the dosed groups. 

3 The time of peak plasma and erythrocyte cholinesterase activity inhibition was 30-60 minutes 

4 after dosing, with recovery to baseline by 3 hours post-dose. Based on a 7% inhibition of 

5 erythrocyte cholinesterase activity, the U.S. EPA set the LOAEL at 0.09 mg/kg. The NOAEL 

6 was 0.06 mg/kg. Erythrocyte cholinesterase activity was inhibited by an average of 28% at 45 

7 minutes post-dose in the 0.15 mg/kg dose group. 

8 

9 3. ANIMAL TOXICITY DATA 

10 

11 Using standard protocols, oxamyl has been tested for ocular and dermal irritation in the 

12 rabbit and dermal sensitization in the guinea pig (IPCS 2002). Oxamyl was not considered an 

13 ocular or dermal irritant and did not induce skin sensitization. The oral LD50 in male and female 

14 rats is 2.5-3.1 mg/kg (Kennedy 1986a). 

15 

16 3.1. Acute Lethality 

17 

18 All inhalation studies were conducted with rats (Table 2). In these studies, atmospheres 

19 of oxamyl were generated as dust or liquid aerosol. In an early study, groups of six young male 

20 ChR-CD rats inhaled 95% pure oxamyl dust, head-only, at concentrations of 140, 160, 180, or 

210 mg/m3 21 for one hour (Kennedy 1986a; see also DuPont 1969a for details of the study). 

22 Groups of six young female ChR-CD rats inhaled oxamyl (95% a.i.) at analytically-determined 

concentrations of 100, 120, or 140 mg/m3 23 , head-only, for one hour. All rats were two months 

24 old at initiation of the study. Particles were suspended by blowing air through a high velocity 

25 glass jet submerged in a mechanically-stirred reservoir of the test dust. Particle size, determined 

26 by cascade impactor sampling, averaged 3.5±2.1μ mass median diameter. All surviving rats 

27 were observed for 14 days post-exposure. During exposure, clinical signs included facial 

28 fasciculations, exophthalmos, lacrimation, red discharge around the nose and eyes, salivation, 

29 and gasping. Survivors lost weight during the first day, but showed normal growth thereafter. 

Calculated 1-hour LC50 values were 170 mg/m3 for male rats and 120 mg/m3 30 for female rats. 

31 

32 In a 4-hour study, groups of six male ChR-CD rats inhaled oxamyl dust (95% a.i.), headonly, at analytically-determined concentrations of 20, 53, 66, 77, or 90 mg/m3 33 (Kennedy 1986a; 

34 DuPont 1969b). Particles were suspended in a 20-liter glass cylinder using a cyclone generator. 

35 Particle size (3.5±2.1μ) was determined by cascade impactor sampling. Male rats exposed to 20 

mg/m3 36 for 4 hours were sacrificed at 1, 2, and 7 days (two rats each day). Major tissues and 

37 organs of these rats were examined grossly and microscopically. Signs displayed during 

38 exposure were intense salivation, facial fasciculations, red discharge around the nose, 

39 lacrimation, exophthalmos, difficulty in breathing, and gasping. Signs were less severe at the 

40 lower concentrations. Deaths generally occurred within one day post-exposure. Following 

41 exposure, surviving rats were pale in color and lost up to 7% body weight. These signs resolved 

42 with no delayed deaths occurring. Except for mild congestion of some organs, results of the 

pathologic examinations of rats exposed to 20 mg/m3 43 were unremarkable on all post-exposure 

days. The four-hour LC50 value for male rats was 64 mg/m3 44 . 

45 

46 In a GLP study that followed U.S. EPA guidelines for acute inhalation studies, groups of 

47 5 male and 5 female Crl:CD rats were exposed, nose-only, to technical oxamyl (98% w/w) dust 
OXAMYL NAC Proposed 1: June 2009/ Page 10 of 36 

at concentrations of 50, 54, 65, or 120 mg/m3 1 for 4 hours (Kelly 2001). Chamber atmospheres of 

2 oxamyl were generated by suspending the particulate test substance with a jetmill. The test 

3 substance was metered into the jetmill with a bin feeder. Filtered, high-pressure air carried the 

4 atmosphere from the jetmill into a 29-L exposure chamber. Chamber concentrations were 

5 controlled by varying the test substance feed rate. Atmosphere concentrations were determined 

6 by gravimetric analysis; HPLC analysis was used to determine the percentage of active 

7 ingredient on the gravimetric filters. Particle size (mass median aerodynamic diameter ) ranged 

8 from 3.2-4.2 μ. 

9 

10 Concentration-related deaths occurred either during exposure or within 2 days of 

11 exposure (Kelly 2001). All rats died at the highest exposure. The LC50 for the sexes combined 

was 56 mg/m3 12 . During exposure, red nasal discharge, gasping, and salivation were observed. 

13 There was a diminished response to an alerting stimulus. Immediately after exposure and during 

14 recovery, clinical signs included lethargy, decreased muscle tone, tremors, spasms, 

15 fasciculations, abnormal posture, abnormal gait, high carriage, and ataxia. Some clinical signs 

16 were seen in all groups. All clinical signs returned to normal in the second week after exposure. 

17 At necropsy, gross observations were unremarkable. 

18 

19 Groups of five male and five female CrL:CD rats inhaled aerosol atmospheres (not 

20 further defined) of a proprietary mixture of oxamyl at concentrations of 160, 220, 240, or 510 

21 mg/m3 for 4 hours (U.S. EPA 1997). Chamber concentrations were based on measured aerosol 

22 concentrations and the reported purity of the active ingredient in the formulation. Rats died 

23 either during exposure or within three days following exposure. Fractional mortalities were 

24 1/10, 2/10, 9/10, and 10/10 at the lowest through highest concentrations, respectively (gender not 

25 provided). Tremors and abnormal gait/mobility were observed in most surviving rats in the 160 

and 220 mg/m3 26 groups. Other clinical signs included gasping, lung noise, irregular respiration, 

27 lethargy, hunched posture, and diarrhea. No further details were provided in the summary 

28 document. 

29 

30 

TABLE 2. Mortality of Rats Exposed to Oxamyl for 1 or 4 Hours 

Exposure Duration/ 

Gender 

Concentration 

(mg/m3

) Mortality 

LC50

(mg/m3

) 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 2001 
OXAMYL 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 

2 3.2. Acute Non-Lethal Toxicity 

3 

4 A study with oxamyl dust addressed non-lethal concentrations (Table 2). Two groups of 

rats, 10 per sex per group, inhaled 0, 4.9 or 24 mg/m3 5 aerosolized oxamyl dust, nose-only, for 4 

6 hours (O’Neil 2000; reviewed in U.S. EPA 2000). Test atmospheres were measured 

7 gravimetrically. Particle size ranged from 0.82 to 1.2 μ. Sacrifice took place immediately after 

8 exposure for cholinesterase activity determination. No deaths occurred during exposure. Wet 

9 stains, ocular/nose discharge and diarrhea were seen in all rats including the control groups. 

Tremors and lethargy were seen in the exposed groups, but incidences in the 4.9 mg/m3 10 group 

11 were similar to those of the control groups (incidence data not reported). Compared to the preexposure values, plasma, erythrocyte and brain cholinesterase activity in males in the 4.9 mg/m3 12 

13 group were inhibited by 12, 28, and 15%, respectively. Respective values for males in the 24 

mg/m3 14 group were 72, 72, and 68%. Compared to the control values, plasma, erythrocyte and 

brain cholinesterase activity in females at 4.9 mg/m3 15 were inhibited by 6.5, 29, and 9%, 

respectively. Respective values for females in the 24 mg/m3 16 group were 76, 73, and 67%. 

17 

18 3.3. Repeat-Exposure Studies

19 

20 No repeat-exposure inhalation studies were located. Repeated-dose oral studies with the 

21 rat show that oxamyl does not accumulate nor do the clinical signs of response change 

22 dramatically following multiple exposures at the same concentration (Kennedy 1986b; IPCS 

23 2002; HSDB 2004). 

24 

25 3.4. Neurotoxicity

26 

27 The studies described in Section 3.1 show that oxamyl is neurotoxic. Clinical signs 

28 included lethargy, decreased muscle tone, tremors, spasms, facial fasciculations, lacrimation, 

29 salivation, abnormal posture and gait, and ataxia. See Section 4.1 for the mode of action of 

30 carbamate insecticides. 

31 

32 In a study of gavage administration of oxamyl to male Long-Evans rats, motor activity 

33 in the period 15 to 35 minutes post-dosing was a reliable predictor of brain and erythrocyte 

34 cholinesterase activity inhibition (McDaniel et al. 2007). Doses were 0, 0.07, 0.10, 0.50, 1.00, 

35 and 1.50 mg/kg. Brain and erythrocyte acetylcholinesterase activity and motor activity were 

36 unaffected at doses of 0.07 and 0.10 mg/kg. Inhibited cholinesterase activity and decreased 

37 motor activity were dose related at >0.10 mg/kg, with brain acetylcholinesterase activity falling 

38 to approximately 40% of the control value and erythrocyte acetylcholinesterase activity and 

39 horizontal and vertical motor activity inhibited to <40% of control. One rat in the 1.00 mg/kg 

40 dose group and two rats in the 1.50 mg/kg dose group showed subtle cholinergic signs. 

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

1 3.5. Developmental/Reproductive Toxicity

2 

3 No inhalation studies were conducted that addressed developmental/reproductive toxicity 

4 of oxamyl. Reproductive and developmental toxicity studies that used the oral route of 

5 administration were reviewed in Kennedy (1986b), IPCS (2002) and HSDB (2004). These 

6 studies are summarized here, demonstrating that oxamyl is not a developmental or reproductive 

7 toxicant even at doses that are maternally toxic. In a two-generation reproductive toxicity study, 

8 male and female CrL-CD rats ingested oxamyl in the diet at doses of 0, 25, 75, or 15.8 ppm 

9 (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 

10 females). F0 rats were mated 74 days after the beginning of treatment to produce the F1

11 generation. The F1 generation was treated for at least 105 days after weaning; dietary 

12 administration continued until weaning of the F2 generation. The NOAEL for parental toxicity 

13 (F0 and F1 parental generation) was 25 ppm. Decreases in body weight, body weight gain, food 

14 consumption and efficiency, and increased relative testis weight were seen at 75 ppm. The 

15 NOAEL for developmental toxicity was also 25 ppm oxamyl in the diet. Reduced pup weight 

16 was seen at 75 ppm during lactation. The NOAEL for reproductive toxicity was 75 ppm. 

17 

18 Similar results were reported in a three-generation oral reproduction study with male and 

19 female CrL-CD rats. Dietary concentrations were 0, 50, 100, or 150 ppm. Oxamyl had no effect 

20 on the number of pregnancies or on gestation or fertility indexes. Dose-dependent reductions in 

21 litter size and body weight of weanlings at 100 and 150 ppm were observed consistently 

22 throughout the study. Individual data were not provided. 

23 

24 In a developmental toxicity study, groups of 25 pregnant Charles River CD BR rats 

25 received doses of 0, 0.2, 0.5, 0.8, or 1.5 mg/kg during gestation days 7-16. Doses were 

26 administered by gavage. The dams were killed on day 22 of gestation and the dams and fetuses 

27 were examined. There were no maternal deaths or abnormal gross changes in the dams. 

28 Maternal toxicity consisting of reduced body weight and reduced food consumption were 

29 observed at 0.8 mg/kg and above, and signs of cholinesterase inhibition were observed at 1.5 

30 mg/kg. Fetal body weight was decreased at 0.8 mg/kg and above. There were no fetal 

31 malformations. 

32 

33 In a developmental toxicity study, groups of 17 pregnant New Zealand rabbits were 

34 gavaged with oxamyl at doses of 0, 1, 2, or 4 mg/kg/day on days 6-19 of gestation. On gestation 

35 day 22, all surviving dams were sacrificed and all fetuses were examined for malformations. 

36 One doe each in the 1 and 4 mg/kg/day groups died; these deaths were attributed to gavage error. 

37 Maternal body weight was reduced at 2 and 4 mg/kg/day, but necropsies were unremarkable. 

38 Although fetal resorptions were increased at 2 and 4 mg/kg/day, no fetal parameters (body 

39 weight, sex ratio, crown-rump length, or external or internal malformations) were statistically 

40 significantly affected. 

41 

42 3.6. Genotoxicity

43 

44 Oxamyl has been tested in a range of in vitro genotoxicity assays (IPCS 2002; HSDB 2004). 

45 No studies addressed genotoxicity in vivo. Most assays were conducted with and without 

46 metabolic activation. Assay results were negative for reverse mutation in Salmonella 

47 typhimurium (TA97a, TA98, TA100, TA1535, TA1537) and Escherichia coli WP2 uvrA. 
OXAMYL NAC Proposed 1: June 2009/ Page 13 of 36 

1 Results were negative for chromosomal aberrations and gene mutations in Chinese hamster 

2 ovary cells, chromosomal aberrations in human lymphocytes, and unscheduled DNA synthesis in 

3 rat hepatocytes. Test concentrations ranged up to 1200 μmol/L. Cytotoxicity was observed at 

4 the higher concentrations. 

5 

6 3.7. Subchronic and Chronic Toxicity/Carcinogenicity 

7 

8 Subchronic and chronic studies employed the dietary route of administration (Kennedy 

9 1986b; IPCS 2002; HSDB 2004). These studies are only briefly described here in order to show 

10 the mode of action and species variability. Male and female CrL-CD Rats fed a diet containing 

11 oxamyl at concentrations of 0, 50, 100, 150, or 500 ppm for 90 days showed signs of 

12 cholinesterase activity inhibition and body weight loss within 2 days at 500 ppm. Dietary 

13 administration at 100 or 150 ppm resulted in reduced body weight gain (up to 7%) without other 

14 clinical signs. No effects were observed at 50 ppm. Feeding of oxamyl at 100 or 150 ppm for 

15 two years also resulted in depressed weight gain. Cholinesterase activity was inhibited only 

16 during the first week of feeding at 150 ppm. There was no tumor response. The NOAEL was 50 

17 ppm (approximately 5 mg/kg/day). 

18 

19 In a similar 90-day feeding study, concentrations of 0, 10, 30, or 250 ppm were 

20 administered in the diet to male and female Crl:CD rats (U.S. EPA 1998). The systemic LOAEL 

21 was 250 ppm based on lower body weight. The LOAEL for neurotoxicity was based on 

22 decreases in brain, plasma, and erythrocyte cholinesterase activity inhibition, and impaired 

23 performance in a Functional Observational Battery at 250 ppm. The NOAEL was 30 ppm. 

24 These dietary concentrations corresponded to 2.1 and 2.4 mg/kg/day (NOAELs for males and 

25 females, respectively) and 14.9 and 19.9 mg/kg/day (LOAELs for males and females, 

26 respectively). 

27 

28 In a two year feeding study, male and female CrL-CD-1 mice were administered diets 

29 containing 0, 25, 50, or 100 ppm (the latter reduced to 75 ppm due to early mortalities). Body 

30 weight of mice fed 50 or 75 ppm was lower than that of controls during the first 6 months of the 

31 study. No other toxic response was seen. There was no evidence of a tumorigenic response. 

32 The NOAEL was 25 ppm in the diet (approximately 2.5 mg/kg/day). 

33 

34 Dogs fed oxamyl at 150 ppm for 2 years showed some clinical chemistry changes but no 

35 inhibition of cholinesterase activity. There were no deaths and no histological changes in major 

36 tissues and organs attributed to the test material. The NOAEL was 100 ppm in the diet 

37 (approximately 2.5 mg/kg/day). 

38 

39 3.8. Summary

40 

41 Acute inhalation lethality studies were conducted with the rat. Toxicity was dependent 

42 on the form of the administered chemical, with the dust being more toxic than the aerosol. The 

1- and 4-hour LC50 values for male rats inhaling the dust were 170 and 64 mg/m3 43 , respectively. 

44 Female rats were more sensitive to the inhalation toxicity of oxamyl dust. The 1- and 4-hour 

LC50 values for female rats were 120 and <50 mg/m3 45 , respectively. The 4-hour LC50 value for 

both sexes combined was 56 mg/m3 46 (Kelly 2001). During exposure, rats showed signs indicative 

47 of acetylcholinesterase activity inhibition. The 4-hour LC50 for an aerosol of oxamyl particulates 
OXAMYL NAC Proposed 1: June 2009/ Page 14 of 36 

was approximately 230 mg/m3 (U.S. EPA 1997). The low vapor pressure of oxamyl (2.3 x 10-4 1 

2 mm Hg at 20-25 oC) makes vapor studies at ambient temperatures impractical. 

3 

4 No evidence of teratogenicity was observed in either the rat or rabbit treated in the diet 

5 with oxamyl (up to 150 ppm) even in the presence of maternal toxicity. A range of genotoxicity 

6 assays all provided negative results. In 2-year feeding studies with the dog, rat, and mouse at 

7 concentrations that approached toxic as indicated by reduced weight gain, there was no evidence 

8 of a tumorigenic response. 

9 

10 4. SPECIAL CONSIDERATIONS

11 4.1. Metabolism and Disposition

12 

13 Inhalation metabolism studies with oxamyl were not located. The N-methyl carbamates 

14 do not have a port of entry effect, are expected to be rapidly absorbed, and do not require 

15 activation (U.S. EPA 2007b). Therefore, relative potency can be estimated from oral studies. 

16 Unlike some organophosphate pesticides that are metabolized by A-esterases which show great 

17 inter-individual variation, the biotransformation of the carbamate pesticides does not involve A18 esterases. Studies of biotransformation in vivo and in vitro following administration by the oral 

19 route or intraperitoneal injection showed that oxamyl is metabolized in rats and mice via two 

20 major pathways: non-enzymatic hydrolysis to the oxime (methyl 2-dimethylamino)-N-hydroxy21 2-ethanimidothioate or DMTO) and enzymatic conversion to dimethylamine(oxo)acetic acid 

(DMOA) (Harvey and Han 1978; IPCS 1983; 2002). Incubation of 14 22 C-labeled oxamyl with rat 

23 or mouse liver homogenate or liver microsomes showed the major fraction of label associated 

24 with the parent compound. Metabolites indicated metabolism by the routes described above. 

25 

When mice were injected intraperitoneally with 14 26 C-labeled oxamyl, urinary metabolites 

27 consisted of the parent compound (16%), DMTO (44%), and a number of other metabolites, 

28 many not identified (Chang and Knowles 1979). In rats treated orally, most radioactivity was 

29 excreted in the urine (Harvey and Han 1978; IPCS 2002). Most of the radioactivity in urine and 

30 feces was recovered as polar conjugates of DMTO, DMOA, and several other metabolites. 

31 According to Costa (2008), most metabolites of carbamic acid ester pesticides are devoid of 

32 biological activity. 

33 

34 Metabolism is fairly rapid as indicated by recovery of brain and erythrocyte 

35 cholinesterase activity following inhibition in rats. In adult Long-Evans rats dosed orally with 1 

36 mg/kg oxamyl, brain and erythrocyte cholinesterase activity were approximately 50 and 20% of 

37 control, respectively at 0.5 hours post-dose; activities in both compartments returned to control 

38 values by 4 hours post-dosing (Padilla et al. 2007). The half-lives for recovery from erythrocyte 

39 cholinesterase activity inhibition in rats and humans are 0.8 and 2.4 hours, respectively, 

40 following oral dosing (U.S. EPA 2007b). 

41 

42 4.2. Mechanism of Toxicity

43 

44 Oxamyl is an N-methyl carbamate insecticide/nematicide. The mode of action of 

45 carbamate pesticides involves cholinesterase inhibition (Costa 2008). Carbamic acid esters 

46 attach to the serine hydroxyl group of the reactive site of acetylcholinesterase, the enzyme 

47 responsible for the destruction and termination of the biological activity of the neurotransmitter 
OXAMYL NAC Proposed 1: June 2009/ Page 15 of 36 

1 acetylcholine. When unbound acetylcholine accumulates at the cholinergic nerve endings, there 

2 is continual stimulation of electrical activity. The resulting signs of toxicity result from 

3 stimulation of the muscarinic receptors of the parasympathetic autonomic nervous system and 

4 are manifest as increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, 

5 diarrhea, urination, and bradycardia. Stimulation of the parasympathetic junctions of the 

6 autonomic nervous system as well as the junctions between nerves and muscles cause 

7 tachycardia, hypertension, muscle fasciculation, tremors, muscle weakness, and flaccid paralysis. 

8 Signs resulting from effects on the central nervous system include restlessness, emotional 

9 lability, ataxia, lethargy, mental confusion, loss of memory, generalized weakness, convulsions, 

10 cyanosis, and coma. Inhibition of acetylcholinesterase activity is transient and reversible 

11 because there is rapid reactivation of the carbamylated enzyme in the presence of water. 

12 

13 Carbamates also inhibit butylcholinesterase, the primary form of cholinesterase found in 

14 blood plasma. The toxicological significance of butylcholinesterase activity inhibition is 

15 unknown. Acetylcholinesterase is the primary form of cholinesterase found in erythrocytes and 

16 is present at neuromuscular and nerve-nerve junctions. A review of studies submitted to U.S. 

17 EPA (2007b) for pesticide registration shows that clinical signs and behavioral effects are not 

18 evident below 10% acetylcholinesterase activity inhibition. Due to human variability, it is 

19 difficult to measure inhibition of <20% from an individual’s baseline (U.S. EPA 2000). At 

20 greater than 30% erythrocyte acetylcholinesterase activity inhibition or 50% plasma activity 

21 inhibition, workers are withdrawn from pesticide application areas (U.S. EPA 2000; ACGIH 

22 2008). Other enzymes such as carboxylesterases are non-target enzymes to which cholinesterase 

23 activity inhibitors may bind. 

24 

25 4.3. Structure-Activity Relationships

26 

27 Organophosphate and carbamate pesticides have a common mode of action (Costa 2008). 

28 Compared to organophosphate ester pesticides, the carbamic acid esters are poor substrates for 

29 cholinesterase-type enzymes. The carbamic acid esters which attach to the reactive site of acetyl 

30 cholinesterase undergo fairly rapid hydrolysis. The carbamylated (inhibited) enzyme is 

31 decarbamylated fairly rapidly with generation of the free, active enzyme. 

32 

33 Information is available on the relative oral toxicity of three carbamate pesticides (HSRB 

34 2006; U.S. EPA 2007b). The endpoints were brain and erythrocyte cholinesterase activity 

35 inhibition in the rat and erythrocyte cholinesterase activity inhibition in humans. Raw data on 

36 erythrocyte cholinesterase activity inhibition were not provided for all three chemicals, but 

37 relative toxicity can be derived from the benchmark doses (BMD10 and BMDL10) calculated by 

38 U.S. EPA (2007b) from a range of oral doses (Table 3). For methomyl and oxamyl, rat data on 

39 brain and erythrocyte cholinesterase activity are presented by McDaniel et al. (2007). If oxamyl 

40 is assigned a relative oral potency factor of 1, then the oral potencies of aldicarb and methomyl 

41 are 4 and 0.67, respectively (U.S. EPA 2007b). 

42 

TABLE 3. Adult Rat and Human BMD10 and BMDL10 Values for Cholinesterase Activity Inhibition by NMethyl Carbamate Pesticides (Oral Dosing) 

Rat Human 

Brain Erythrocyte Erythrocyte 

Chemical Benchmark Half-life Benchmark Half-life Benchmark Half-life 
OXAMYL NAC Proposed 1: June 2009/ Page 16 of 36 

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

Aldicarb BMD10: 0.052 

BMDL10: 0.035 

1.5 BMD10: 0.031 

BMDL10: 0.020 

1.1 BMD10: 0.016 

BMDL10: 0.013 

1.7 

Methomyl BMD10: 0.486 

BMDL10: 0.331 

1.0 BMD10: 0.204 

BMDL10: 0.112 

0.8 BMD10: 0.040 

BMDL10: 0.028 

1.6 

Oxamyl BMD10: 0.165 

BMDL10: 0.127 

0.9 BMD10: 0.278 

BMDL10: 0.158 

0.8 BMD10: 0.083 

BMDL10: 0.068 

2.4 

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

2 female rat values. 

3 The BMDL10 for 10% brain cholinesterase activity inhibition was used as the point of departure for U.S. EPA 

4 (2007b) risk assessment. 

5 Source: Table 1.B-9, p. 50, U.S. EPA 2007b.

6 

7 4.4. Other Relevant Information

8 4.4.1. Species Variability

9 

10 The extent of hydrolysis of carbamate ester insecticides varies among species, ranging 

11 from 30 to 95%, and is chemical specific (Costa 2008). Baseline erythrocyte 

12 acetylcholinesterase activity is higher in humans than in other species (Ellin 1981). 

13 

14 Inhalation studies were conducted only with rats. Subchronic and chronic feeding studies 

15 with the rat, mouse, and dog showed little difference in toxicity among the species. Based on 

16 differences in modeled values for erythrocyte acetylcholinesterase activity inhibition between 

17 rats and humans, the U.S. EPA Office of Pesticide Programs calculated an oxamyl-specific 

18 inhalation interspecies uncertainty factor of 3 (U.S. EPA 2007b). Half-lives for enzyme 

19 regeneration of erythrocyte cholinesterase activity were 0.8 hours (adult rats) and 2.4 hours 

20 (humans). 

21 

22 4.4.2. Susceptible Populations

23 

24 Humans vary by gender, age, and genetic make-up in sensitivity to cholinesterase 

25 inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 activity units; 

26 acetylthiocholine substrate) is greater than that of healthy newborn infants (97±15 activity units) 

27 by a factor of 1.6 (Herz et al. 1975). Developmental neurotoxicity studies showed that 

28 protection of the rat dam against cholinesterase activity inhibition is protective against pup 

29 acetylcholinesterase activity inhibition in utero. The U.S. EPA (2007b) identified infants and 

30 juveniles as the most sensitive population to the anticholinesterase effects of N-methyl carbamate 

31 pesticides. In so doing, they evaluated the relative sensitivity of juvenile and adult rats to N32 methyl carbamate pesticides including oxamyl. Based on comparative brain acetylcholinesterase 

33 activity inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated a 

34 Food Quality Protection Act (FQPA) uncertainty factor of 3.48 for children. This uncertainty 

35 factor corresponds to an AEGL intraspecies uncertainty factor. 

36 

37 4.4.3. Concentration-Exposure Duration Relationship

38 

39 The concentration-time relationship for a single endpoint for many irritant and 

systemically acting inhalational toxicants may be described by Cn 40 x t = k (ten Berge et al. 1986). 

41 Data for time-scaling from three studies (DuPont 1969a; DuPont 1969b; Kelly 2001) and two 
OXAMYL NAC Proposed 1: June 2009/ Page 17 of 36 

1 exposure durations (1 and 4 hours) provided consistent results. The least squares derived line 

2 describing the slope between the 1 and 4-hour values has an n value of 1.6 (Appendix A). 

3 

4 4.4.4. Concurrent Exposure Issues

5 

6 No information relevant to concurrent exposure issues was located. Dermal absorption 

7 may occur, but toxicity is low compared to inhalation exposure as indicated by a dermal LD50 in 

8 rabbits of >2000 mg/kg body weight (IPCS 2002). 

9 

10 5. DATA ANALYSIS FOR AEGL-1

11 5.1. Summary of Human Data Relevant to AEGL-1

12 

13 No human inhalation studies were located in the available literature. No occupational 

14 monitoring data were presented by U.S. EPA (2007a). 

15 

16 5.2. Summary of Animal Data Relevant to AEGL-1

17 

18 One study with oxamyl dust was available. In that study, groups of 10 rats/sex inhaled 

4.9 or 24 mg/m3 19 of oxamyl dust for 4 hours (O’Neil 2000; U.S. EPA 2000). Plasma, erythrocyte, 

20 and brain cholinesterase activity were inhibited at both concentrations. For the sexes combined, 

21 brain cholinesterase activity inhibition averaged 12% and erythrocyte acetylcholinesterase 

22 activity inhibition averaged 28.5% at the lower concentration. Respective values were 67.5% 

23 and 72.5% at the higher concentration. 

24 

25 5.3. Derivation of AEGL-1

26 

27 The key study for AEGL-1 determination was O’Neil (2000; U.S. EPA 2000). Inhalation 

of 4.9 mg/m3 28 oxamyl dust for 4 hours inhibited erythrocyte acetylcholinesterase activity by 

29 28.5% (average of values in males and females) and brain cholinesterase by 12% (average of 

30 values in males and females). Erythrocyte acetylcholinesterase activity inhibition of that 

31 magnitude may result in transient symptoms of discomfort in humans. Wet stains, ocular/nose 

discharge and diarrhea were seen in rats exposed to 4.9 and 24 mg/m3 32 as well as in the control 

33 groups. Additionally tremors and lethargy were seen in the exposed groups, but incidences in 

the 4.9 mg/m3 34 group were reported as similar to those of the control groups (incidence data not 

35 reported). U.S. EPA (2007b) derived an interspecies uncertainty factor of 3 for oxamyl based on 

36 differences in modeled values for erythrocyte acetylcholinesterase activity inhibition between 

37 rats and humans (See section 4.4.1). Based on comparative brain cholinesterase activity 

38 inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated an 

39 intraspecies uncertainty factor of 3.48 to protect sensitive young (See section 4.4.2). The 

40 combined uncertainty factor is 10.4 (rounded to 10). Female rats were not more sensitive to 

oxamyl exposure than male rats in this study. Values were time-scaled (Cn 41 x t = k) from the 4-

42 hour data point using an n value of 1.6. Values are summarized in Table 4. Calculations are in 

43 Appendix B, and a category graph of the toxicity data in relation to AEGL values is in Appendix 

44 D. 

45 

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

10-min 30-min 1-h 4-h 8-hour 

3.6 mg/m3 1.8 mg/m3 1.2 mg/m3 0.49 mg/m3 0.32 mg/m3

1 

2 6. DATA ANALYSIS FOR AEGL-2

3 6.1. Summary of Human Data Relevant to AEGL-2

4 

5 No human inhalation studies were located in the available literature. 

6 

7 6.2. Summary of Animal Data Relevant to AEGL-2

8 

9 No animal studies relevant to deriving AEGL-2 values were located in the available 

10 literature. All studies reviewed in Section 3.1 involved mortality. 

11 

12 6.3. Derivation of AEGL-2

13 

14 No data on an oxamyl dust concentration that would result in effects consistent with the 

15 definition of an AEGL-2 were available in the open literature. Therefore, AEGL-2 values were 

16 derived by dividing the AEGL-3 values by 3. This approach is justified when there is a steep 

17 concentration-response curve (NRC 2001). As shown by the study of Kelly (2001) mortality 

went from 0% at 50 mg/m3 to 100% when concentration was increased 2.4-fold (120 mg/m3 18 ). 

19 AEGL-2 values are summarized in Table 5. Calculations are in Appendix B and a category 

20 graph of the toxicity data in relation to AEGL values is in Appendix D. 

21 

TABLE 5. AEGL-2 Values for Oxamyl

10-min 30-min 1-h 4-h 8-h 

5.3 mg/m3 2.7 mg/m3 1.8 mg/m3 0.73 mg/m3 0.47 mg/m3

22 

23 

24 7. DATA ANALYSIS FOR AEGL-3

25 7.1. Summary of Human Data Relevant to AEGL-3

26 

27 No human inhalation studies relevant to development of AEGL-3 values were located in 

28 the available literature. 

29 

30 7.2. Summary of Animal Data Relevant to AEGL-3

31 

32 Because of its low vapor pressure, concentrations of oxamyl vapor high enough to induce 

33 mortality could not be attained. Three studies with oxamyl dust addressed lethality in the rat. In 

a 1-hour study LC50 values for male and female rats were 170 and 120 mg/m3 34 , respectively 

(DuPont 1969a). The 4-hour LC50 in male and female rats combined was 64 mg/m3 35 (DuPont 

1969b). A more recent study with rats reported a similar 4-hour LC50 value, 56 mg/m3 36 (Kelly 

37 2001). 

38 

39 7.3. Derivation of AEGL-3

40 

41 Studies with oxamyl dust were chosen for development of AEGL values. The more 

42 recent, GLP study of Kelly (2001) was chosen as the basis for development of AEGL-3 values. 
OXAMYL NAC Proposed 1: June 2009/ Page 19 of 36 

The calculated 1-hour BMCL05 for lethality is 22 mg/m3 and the BMC01 is 33 mg/m3 1 (Appendix 

2 C). The NAC/AEGL Committee generally uses the BMCL05 as the estimate at which lethality is 

3 not likely to be observed (NRC 2001). U.S. EPA (2007b) derived an interspecies uncertainty 

4 factor of 3 for oxamyl based on differences in values for erythrocyte acetylcholinesterase activity 

5 inhibition between rats and humans (See section 4.4.1). Based on comparative brain 

6 cholinesterase activity inhibition in post-natal day 11 juvenile rats and adult rats, the U.S. EPA 

7 calculated an uncertainty factor of 3.48 to protect sensitive young (See section 4.4.2). The 

8 combined uncertainty factor is 10.4 (rounded to 10) Although female rats appear to be slightly 

9 more sensitive to the toxic effects of oxamyl than male rats, the combined data with application 

10 of an uncertainty factor that protects sensitive juveniles provides a reasonable estimate of 

lethality. Values were time-scaled (Cn 11 x t = k) from the 4-hour data point using an n value of 

12 1.6. Values are summarized in Table 6, calculations are in Appendix B, and a category graph of 

13 the toxicity data in relation to AEGL values is in Appendix D. 

14 

TABLE 6. AEGL-3 Values for Oxamyl

10-min 30-min 1-h 4-h 8-h 

16 mg/m3 8.2 mg/m3 5.3 mg/m3 2.2 mg/m3 1.4 mg/m3

15 

The 4-hour LC50 for rats in the key study (Kelly 2001) is 56 mg/m3 16 . A similar 4-hour 

LC50 value (64 mg/m3 17 ) for rats was identified in a study conducted 30 years earlier in the same 

18 laboratory (DuPont 1969b). 

19 

20 8. SUMMARY OF AEGLs

21 8.1. AEGL Values and Toxicity Endpoints 

22 

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

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/m3 1.8 mg/m3 1.2 mg/m3 0.49 mg/m3 0.32 mg/m3

AEGL-2 

(Disabling) 

5.3 mg/m3 2.7 mg/m3 1.8 mg/m3 0.73 mg/m3 0.47 mg/m3

AEGL-3 

(Lethal) 

16 mg/m3 8.2 mg/m3 5.3 mg/m3 2.2 mg/m3 1.4 mg/m3

25 

26 

27 8.2. Comparison with Other Standards and Guidelines 

28 

29 Other than AEGLs, no inhalation standards or guidelines for oxamyl have been established 

30 (Table 8). For acetylcholinesterase inhibiting chemicals in general, the American Conference of 

31 Governmental Industrial Hygienists has established a Biological Exposure Index based on 

32 erythrocyte cholinesterase activity (ACGIH 2008). Individuals should leave the area when their 

33 erythrocyte acetylcholinesterase activity falls to 70% of their baseline. 

34 
OXAMYL NAC Proposed 1: June 2009/ Page 20 of 36 

 The U.S. EPA (2007b) calculated inhalation BMD10 values of 5 and 2 mg/m3 1 for brain and 

2 erythrocyte cholinesterase inhibition, respectively, in humans. The endpoint was a 10% 

3 inhibition of erythrocyte cholinesterase activity. 

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/m3 1.8 mg/m3 1.2 mg/m3 0.49 mg/m3 0.32 mg/m3

AEGL-2 5.3 mg/m3 2.7 mg/m3 1.8 mg/m3 0.73 mg/m3 0.47 mg/m3

AEGL-3 16 mg/m3 8.2 mg/m3 5.3 mg/m3 2.2 mg/m3 1.4 mg/m3

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 7 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association 

8 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 

9 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 

10 perceiving a clearly defined objectionable odor. 

11 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 

12 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 

13 symptoms that could impair an individual=s ability to take protective action. 

14 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 

15 exposed for up to one hour without experiencing or developing life-threatening health effects. 

16 b 17 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) 

18 represents the maximum concentration from which one could escape within 30 minutes without any escape19 impairing symptoms, or any irreversible health effects. 

20 c 21 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 

22 Time Weighted Average) is defined analogous to the ACGIH-TLV-TWA. 

23 d 24 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 

25 Weighted Average) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 

26 hours/day, 40 hours/week. 

27 e 28 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 

29 Time Weighted Average) is the time-weighted average concentration for a normal 8-hour workday and a 40-hour 

30 workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. 

31 

32 fMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche 

33 Forschungsgemeinschaft [German Research Association] is defined analogous to the ACGIH-TLV-TWA. 

34 
OXAMYL NAC Proposed 1: June 2009/ Page 21 of 36 

1 gMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 

2 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands) is defined similar to the 

3 ACGIH TLV. 

4 

5 8.3. Data Adequacy and Research Needs

6 

7 Oxamyl has a low vapor pressure and no suitable inhalation exposure studies with 

8 humans were located in the available literature. An oral dosing study with human volunteers 

9 addressed effects consistent with cholinesterase activity inhibition. Inhalation studies with rats 

10 as the test species and involving two time points and dust and aerosol delivery were sufficient for 

11 derivation of three AEGL levels for five timepoints. Studies involving comparisons of 

12 cholinesterase activity inhibition between juvenile and adult rats and between rats and humans 

13 addressed chemical-specific uncertainty factors. Metabolism pathways and mode of action are 

14 well understood. 

15 

16 9. REFERENCES

17 

18 ACGIH (American Conference of Government and Industrial Hygienists). 2008. TLVs and BEIs Based 

19 on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & 

20 Biological Exposure Indices. Cincinnati, OH: ACGIH. 

21 

22 Chang, K.M., and C.O. Knowles. 1979. Metabolism of oxamyl in mice and two-spotted spider mites. 

23 Arch. Environ. Contam. Toxicol. 8:499-508. 

24 

25 Costa, L.G. 2008. Chapter 22: Toxic Effects of Pesticides. In Casarett & Doull’s Toxicology, The Basic 

Science of Poisons. 7th 26 Ed. New York: McGraw-Hill. 

27 

28 DuPont. 1969a. One-Hour Inhalation Toxicity, Haskell Laboratory Report No. 281-69. Haskell 

29 Laboratory for Toxicology and Industrial Medicine, Newark, DE. (Same as Tayfun 1969b). 

30 

31 DuPont. 1969b. Acute Dust Inhalation Toxicity. Haskell Laboratory Report No. 280-69. Haskell 

32 Laboratory for Toxicology and Industrial Medicine, Newark, DE. (Same as Tayfun 1969a). 

33 

34 Ellin, R.I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorus 

35 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 

36 Biomedical Laboratory Report No. USABML-SP-81-003. Available from the Defense Technical 

37 Information Center, AD A1013364. 

38 

39 Harvey, J., Jr., and J. C-Y. Han. 1978. Metabolism of oxamyl and selective metabolites in the rat. J. 

40 Agric. Food Chem. 26:902-910. 

41 

42 Herz, F., E. Kaplan, and E.S. Scheye. 1975. A longitudinal study of red cell enzymes in infants of low 

43 birth weight. Z. Kinderheilk. 120: 217-221. 

44 

45 HSDB (Hazardous Substances Data Bank). 2004. Oxamyl. Available online: 

46 http://toxnet/nlm.nih.gov/cgi-bin/sis/download.txt. 

47 

48 HSRB (Human Studies Review Board). 2006. Report of the Human Studies Review Board April 4-6, 

49 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 

50 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting51 materials/apr-4-6-2006-public-meeting/april2006mtgfinalreport62606.pdf. 
OXAMYL NAC Proposed 1: June 2009/ Page 22 of 36 

1 

2 IPCS (International Program on Chemical Safety). 1983. Data Sheets on Pesticides No. 54: Oxamyl. 

3 World Health Organization. Available online: 

4 http://www.inchem.org/documents/pds/pds/pest54_e.htm. 

5 

6 IPCS (International Program on Chemical Safety). 2002. Pesticide residues in food – 2002- Joint 

7 FAO/WHO Meeting on Pesticide Residues; Oxamyl. World Health Organization. Available online: 

8 http://www.inchem.org/documents/jmpr/jmpmono/2002pr11.htm. 

9 

10 Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation Median Lethal Concentration 

11 (LC50) Study in Rats. E.I. du Pont de Nemours and Co., Haskell Laboratory for Toxicology and 

12 Industrial Medicine, Newark, DE; Laboratory Project ID: DuPont-6331. 

13 

14 Kennedy, G.L., Jr. 1986a. Acute toxicity studies with oxamyl. Fundam. Appl. Toxicol. 6:423-429. 

15 

16 Kennedy, G.L., Jr. 1986b. Chronic toxicity, reproductive, and teratogenic studies with oxamyl. Fundam. 

17 Appl. Toxicol. 7:106-118. 

18 

19 McDaniel, K.L., S. Padilla, R.S. Marshall, P.M. Phillips, L. Podhorniak, Y. Qian, and V.C. Moser. 2007. 

20 Comparison of acute neurobehavioral and cholinesterase inhibitory effects of N-methylcarbamates in 

21 rat. Toxicol. Sci. 98:552-560. 

22 

23 McFarlane, P. and S. Freestone. 1999. A randomized double blind ascending oral dose study with 

24 oxamyl. Inveresk Clinical Research, Riccarton, Edinburgh, Scotland. Laboratory Project ID: HLO25 1998-01505, August 10, 1999. Reviewed in U.S. EPA 2005. 

26 

27 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 

28 Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. 

29 

30 O’Neil, A.J. 2000. Cholinesterase Inhibition Determined in Rats Exposed to Inhalation Atmospheres of 

31 Oxamyl Technical (96.9%). Haskell Laboratory of Toxicology and Industrial Medicine, E.I. du Pont 

32 de Nemours Co. DuPont Study No. 4383. (Reviewed in U.S. EPA 2000, MRID 45155801). 

33 

34 O’Neil, M.J., A. Smith, and P.E. Heckelman. 2001. Oxamyl. The Merck Index. Whitehouse Station, 

35 NJ: Merck & Co., Inc., p. 6994. 

36 

37 Padilla, S., R.S. Marshall, D.L. Hunter, and A. Lowit. 2007. Time course of cholinesterase inhibition in 

38 adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, or 

39 propoxur. Toxicol. Appl. Pharmacol. 219:202-209. 

40 

41 RTECS (Registry of Toxic Effects of Chemical Substances). 2008. Canadian Centre for Occupational 

42 Health and Safety, MDL Information Systems, Inc.. Available online: http://www.ccohs.ca/. 

43 

44 Tayfun, F.O. 1969a. Acute dust inhalation toxicity (ChR-CD rats – head only- four hours). Unpublished 

45 DuPont Haskell Laboratory Report HLR 280-69). E.I. duPont de Nemours & Co., Wilmington, DE. 

46 

47 Tayfun, F.O. 1969b. One-hour inhalation toxicity (ChR-CD rats – head only). Unpublished DuPont 

48 Haskell Laboratory Report HLR 281-69). E.I. duPont de Nemours & Co., Wilmington, DE. 

49 

50 ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response 

51 relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13: 301-309. 

52 
OXAMYL NAC Proposed 1: June 2009/ Page 23 of 36 

1 U.S. EPA (U.S. Environmental Protection Agency). 1997. Initial Submission: Letter from [name 

2 deleted] to USEPA Reporting Results of Acute Inhalation Study of Oxamyl in Rats, Dated 5/23/1997 

3 (Sanitized). OTS0559122, available from National Technical Information Service, Springfield, VA. 

4 

5 U.S. EPA (U.S. Environmental Protection Agency). 1998. Data Evaluation Record: Oxamyl (MRID 

6 44504901). Available online: Regulations.gov/oxamyl 103801. Citation: E.I. duPont de Nemours 

7 and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, Newark, 

8 DE. Laboratory Project ID: HL-1998-00708, February 23, 1998. 

9 

10 U.S. EPA (U.S. Environmental Protection Agency). 2000. Data Evaluation Record: Oxamyl (MRID 

11 45155801). Citation: O’Neil, A.J. 2000. Cholinesterase inhibition determined in rats exposed to 

12 inhalation atmospheres of oxamyl technical (96.9%). Haskell Laboratory of Toxicology and 

13 Industrial Medicine, E.I. du Pont de Nemours Co. DuPont Study No. 4383. 

14 

15 U.S. EPA (U.S. Environmental Protection Agency). 2005. Data Evaluation Record: Oxamyl/103801 

16 (MRID 44912301). Available online: Regulations.gov/oxamyl 103801. Citation: McFarlane, P. and 

17 S. Freestone. 1999. A randomized double blind ascending oral dose study with oxamyl. Inveresk 

18 Clinical Research, Riccarton, Edinburgh, Scotland. Laboratory Project ID: HLO-1998-01505, 

19 August 10, 1999. 

20 

21 U.S. EPA (U.S. Environmental Protection Agency). 2007a. Reregistration Eligibility Decision (RED) 

22 for Oxamyl. Available online: www.epa.gov/pesticides/reregistration/REDs/oxamyl_red.pdf. 

23 

24 U.S. EPA (U.S. Environmental Protection Agency). 2007b. Revised N-Methyl Carbamate Cumulative 

25 Risk Assessment. Office of Pesticide Programs. Available online: 

26 http://www.epa.gov/oppsrrd1/REDs/nmc_revised_cra.pdf. 

27 

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

1 

2 APPENDIX A: Time-Scaling Calculation for Oxamyl AEGLs 

3 

1.7 

1.8 

1.9 

2 

2.1 

2.2 

2.3 

Log 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 

6 Time scaling of LC50 values was based on the 1-hour study of DuPont 1969a and the 4-hour studies of 

7 DuPont 1969b and Kelly 2001. 

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 

9 n = 1.59 

10 k = 163526.7 

11 
OXAMYL NAC Proposed 1: June 2009/ Page 25 of 36 

1 

2 APPENDIX B: Derivation of Oxamyl AEGLs 

3 

4 Derivation of AEGL-1 Values 

5 

6 Key Study: O’Neil, A.J. 2000. Cholinesterase Inhibition determined in Rats Exposed to 

7 Inhalation Atmospheres of Oxamyl Technical (96.9%). Haskell Laboratory 

8 of Toxicology and Industrial Medicine, E.I. du Pont de Nemours Co. DuPont 

9 Study No. 4383. (Summarized in U.S. EPA 2000). 

10 

11 Toxicity endpoint: Clinical signs of ocular/nasal discharge, diarrhea, tremors, and lethargy (the 

12 latter two signs also seen in control rats) following a 4-hour exposure of rats 

to 4.9 mg/m3 13 . For the sexes combined, brain cholinesterase activity 

14 inhibition averaged 12% and erythrocyte acetylcholinesterase activity 

15 inhibition averaged 28.5%. 

16 

Time scaling Cn 17 x t = k where n = 1.6 based on time scaling from the 1- and 4-hour rat data 

18 (three studies) with oxamyl dust. 

19 

20 Uncertainty factors: Total uncertainty factor: 10 

21 Interspecies: 3 – The U.S. EPA (2007b) Office of Pesticide Programs 

22 calculated an oxamyl-specific inhalation interspecies uncertainty 

23 factor of 3 based on differences in values for erythrocyte 

24 acetylcholinesterase activity inhibition between rats and humans. 

25 Intraspecies: 3.48 – The U.S. EPA (2007b) Office of Pesticide 

26 Programs calculated an oxamyl-specific inhalation intraspecies 

27 uncertainty factor of 3.48 based on comparative brain 

28 acetylcholinesterase activity inhibition in post-natal day 11 juvenile 

29 rats and adult rats. 

30 

31 Modifying factor: None applied 

32 

Calculations: (4.9 mg/m3/10)1.6 x 240 minutes = 76.65 mg/m3(1.6) 33 •min 

34 

10-min AEGL-1: C = 1.6√(76.65 mg/m3(1.6)•min/10) = 3.6 mg/m3 35 

36 

30-min AEGL-1: C = 1.6√(76.65 mg/m3(1.6)•min/30) = 1.8 mg/m3 37 

38 

1-h AEGL-1: C = 1.6√(76.65 mg/m3(1.6)•min/60) = 1.2 mg/m3 39 

40 

4-h AEGL-1: C = 4.9 mg/m3/10 = 0.49 mg/m3 41 

42 

8-h AEGL-1: C = 1.6√(76.65 mg/m3(1.6)•min/480) = 0.32 mg/m3 43 

44 

45 
OXAMYL NAC Proposed 1: June 2009/ Page 26 of 36 

1 

2 Derivation of AEGL-2 Values

3 

4 Key Study: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation 

5 Median Lethal Concentration (LC50) Study in Rats. E.I. du Pont de Nemours 

6 and Co., Haskell Laboratory for Toxicology and Industrial Medicine, 

7 Newark, DE; Laboratory Project ID: DuPont-6331. 

8 

9 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentration-response line shown 

10 by the Kelly (2001) data justifies deriving AEGL-2 values by dividing the 

11 AEGL-3 values by 3 (NRC 2001). 

12 

Time scaling Cn 13 x t = k where n = 1.6 based on time scaling from the 1- and 4-hour rat data 

14 (three studies) with oxamyl dust. 

15 

16 Uncertainty factors: Total uncertainty factor: 10 (See AEGL-3 below) 

17 

18 Calculations: AEGL-3 values/3 

19 

10-min AEGL-2: C = 16/3 = 5.3 mg/m3 20 

21 

30-min AEGL-2: C = 8.2/3 = 2.7 mg/m3 22 

23 

1-h AEGL-2: C = 5.3/3 = 1.8 mg/m3 24 

25 

4-h AEGL-2: C = 2.2/3 = 0.73 mg/m3 26 

27 

8-h AEGL-2: C = 1.4/3 = 0.47 mg/m3 28 

29 
OXAMYL NAC Proposed 1: June 2009/ Page 27 of 36 

1 

2 Derivation of AEGL-3 Values

3 

4 Key Study: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation 

5 Median Lethal Concentration (LC50) Study in Rats. E.I. du Pont de Nemours 

6 and Co., Haskell Laboratory for Toxicology and Industrial Medicine, 

7 Newark, DE; Laboratory Project ID: DuPont-6331. 

8 

Toxicity endpoint: Threshold for lethality in rats at the BMCL05 of 22.2692 mg/m3 9 calculated 

10 from the rat lethality data of Kelly (2001). 

11 

Time scaling Cn 12 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 

16 Interspecies: 3 – The U.S. EPA Office of Pesticide Programs (2007b) 

17 calculated an oxamyl-specific inhalation interspecies uncertainty 

18 factor of 3 based on differences in values for erythrocyte 

19 cholinesterase activity inhibition between rats and humans. 

20 Intraspecies: 3.48 – The U.S. EPA Office of Pesticide Programs 

21 (2007b) calculated an oxamyl-specific inhalation intraspecies 

22 uncertainty factor of 3.48 based on comparative brain 

23 acetylcholinesterase activity inhibition in post-natal day 11 juvenile 

24 rats and adult rats. 

25 

26 Modifying factor: None applied 

27 

Calculations: (22.27 mg/m3/10)1.6 x 240 minutes = 864.05 mg/m3(1.6) 28 •min 

29 

10-min AEGL-3: C = 1.6√(864.05 mg/m3(1.6)•min/10) = 16 mg/m3 30 

31 

30-min AEGL-3: C = 1.6√(864.05 mg/m3(1.6)•min/30) = 8.2 mg/m3 32 

33 

1-h AEGL-3: C = 1.6√(864.05 mg/m3(1.6)•min/60) = 5.3 mg/m3 34 

35 

4-h AEGL-3: C = 22.27/10 = 2.2 mg/m3 36 

37 

8-h AEGL-3: C = 1.6√(864.05 mg/m3(1.6)•min/480) = 1.4 mg/m3 38 

39 

40 
OXAMYL NAC Proposed 1: June 2009/ Page 28 of 36 

1 APPENDIX C: Benchmark Concentration Calculations for Oxamyl 

2 

3 Calculation of BMC01: Data of Kelly 2001 

4 ============================================================== 

5 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 

6 Input Data File: C:\BMDS\OXAMYL _RAT.(d) 

7 Gnuplot Plotting File: C:\BMDS\OXAMYL _RAT.plt 

8 Wed Feb 25 13:36:33 2009 

9 ============================================================== 

10 

11 BMDS MODEL RUN 

12 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

13 

14 The form of the probability function is: 

15 

16 P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

17 

18 where CumNorm(.) is the cumulative normal distribution function 

19 

20 Dependent variable = COLUMN3 

21 Independent variable = COLUMN1 

22 Slope parameter is not restricted 

23 

24 Total number of observations = 5 

25 Total number of records with missing values = 0 

26 Maximum number of iterations = 250 

27 Relative Function Convergence has been set to: 1e-008 

28 Parameter Convergence has been set to: 1e-008 

29 

30 User has chosen the log transformed model 

31 

32 Default Initial (and Specified) Parameter Values 

33 background = 0 

34 intercept = -9.7974 

35 slope = 2.42048 

36 

37 Asymptotic Correlation Matrix of Parameter Estimates 

38 

39 ( *** The model parameter(s) -background 

40 have been estimated at a boundary point, or have been specified by the user, 

41 and do not appear in the correlation matrix ) 

42 

43 intercept slope 

44 intercept 1 -1 

45 slope -1 1 

46 Parameter Estimates 

47 Variable Estimate Std. Err. 

48 background 0 NA 

49 intercept -17.86 8.42225 

50 slope 4.43819 2.09164 

51 

52 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no 
OXAMYL NAC Proposed 1: June 2009/ Page 29 of 36 

1 standard error. 

2 

3 Analysis of Deviance Table 

4 Model Log(likelihood) Deviance Test DF P-value 

5 Full model -17.8428 

6 Fitted model -18.7358 1.78596 3 0.618 

7 Reduced model -34.6574 33.6292 4 <.0001 

8 

9 AIC: 41.4715 

10 

11 Goodness of Fit Scaled 

12 Dose Est._Prob. Expected Observed Size Residual 

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

14 0.0000 0.0000 0.000 0 10 0 

15 50.0000 0.3093 3.093 2 10 -0.748 

16 54.0000 0.4379 4.379 6 10 1.033 

17 65.0000 0.7475 7.475 7 10 -0.3458 

18 120.0000 0.9996 9.996 10 10 0.05937 

19 

20 Chi-square = 1.75 DF = 3 P-value = 0.6260 

21 

22 Benchmark Dose Computation 

23 

24 Specified effect = 0.01 

25 Risk Type = Extra risk 

26 Confidence level = 0.95 

27 

28 BMC01 = 33.1158 

29 

30 BMCL01 = 15.6441 

31 

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

13:36 02/25 2009

BMDL BMD

 

Probit

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

1 Calculation of BMCL05: Data of Kelly 2001 

2 ============================================================== 

3 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 

4 Input Data File: C:\BMDS\OXAMYL _RAT.(d) 

5 Gnuplot Plotting File: C:\BMDS\OXAMYL _RAT.plt 

6 Wed Feb 25 13:36:33 2009 

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

8 BMDS MODEL RUN 

9 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

10 The form of the probability function is: P[response] = Background + (1-Background) * CumNorm 

11 (Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function 

12 

13 Dependent variable = COLUMN3 

14 Independent variable = COLUMN1 

15 Slope parameter is not restricted 

16 

17 Total number of observations = 5 

18 Total number of records with missing values = 0 

19 Maximum number of iterations = 250 

20 Relative Function Convergence has been set to: 1e-008 

21 Parameter Convergence has been set to: 1e-008 

22 

23 User has chosen the log transformed model 

24 

25 Default Initial (and Specified) Parameter Values 

26 background = 0 

27 intercept = -9.7974 

28 slope = 2.42048 

29 

30 Asymptotic Correlation Matrix of Parameter Estimates 

31 

32 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been 

33 specified by the user, and do not appear in the correlation matrix ) 

34 

35 intercept slope 

36 

37 intercept 1 -1 

38 

39 slope -1 1 

40 

41 Parameter Estimates 

42 

43 Variable Estimate Std. Err. 

44 background 0 NA 

45 intercept -17.86 8.42225 

46 slope 4.43819 2.09164 

47 

48 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no 

49 standard error. 

50 

51 Analysis of Deviance Table 

52 
OXAMYL NAC Proposed 1: June 2009/ Page 31 of 36 

1 Model Log(likelihood) Deviance Test DF P-value 

2 Full model -17.8428 

3 Fitted model -18.7358 1.78596 3 0.618 

4 Reduced model -34.6574 33.6292 4 <.0001 

5 

6 AIC: 41.4715 

7 

8 Goodness of Fit 

9 Scaled 

10 Dose Est._Prob. Expected Observed Size Residual 

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

12 0.0000 0.0000 0.000 0 10 0 

13 50.0000 0.3093 3.093 2 10 -0.748 

14 54.0000 0.4379 4.379 6 10 1.033 

15 65.0000 0.7475 7.475 7 10 -0.3458 

16 120.0000 0.9996 9.996 10 10 0.05937 

17 

18 Chi-square = 1.75 DF = 3 P-value = 0.6260 

19 

20 Benchmark Dose Computation 

21 

22 Specified effect = 0.05 

23 Risk Type = Extra risk 

24 Confidence level = 0.95 

25 

26 BMC05 = 38.612 

27 

28 BMCL05 = 22.2692 

29 

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

13:42 02/25 2009

BMDL BMD

 

Probit

30 

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

1 APPENDIX D: Category Graph of AEGL Values and Toxicity Data 

2 

0 

1 

10 

100 

1000 

 mg/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 

6 Data: 

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

 

 Source Species mg/m3 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 AEGL 
OXAMYL 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) 

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

1 

2 APPENDIX E: Derivation Summary for Oxamyl AEGLs 

3 Acute Exposure Guideline Levels For Oxamyl 

4 (CAS Reg. No. 23135-22-0) 

5 

AEGL-1 VALUES

10-min 30-min 1-h 4-h 8-hour 

3.6 mg/m3 1.8 mg/m3 1.2 mg/m3 0.49 mg/m3 0.32 mg/m3

Key Reference: O’Neil, A.J. 2000. Cholinesterase Inhibition 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/m3/4 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/m3

for 4 hours meet the definition of an AEGL-1. Inhalation of 4.9 mg/m3

 oxamyl dust for 4 hours inhibited 

erythrocyte acetylcholinesterase activity by 28.5% (average 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 Pesticide Programs calculated an oxamyl-specific 

inhalation interspecies uncertainty factor of 3 based on comparative erythrocyte cholinesterase activity 

inhibition in rats and humans. 

Intraspecies: 3.48, The U.S. EPA (2007b) Office of Pesticide Programs calculated an oxamyl-specific 

inhalation intraspecies uncertainty factor of 3.48 based 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: Cn x t = k, where n = 1.6 calculated from three lethality studies 

Data Adequacy: The key study was well-conducted, used adequate numbers of rats, and provided analytical 

concentrations. 

6 

7 
OXAMYL 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/m3 2.7 mg/m3 1.8 mg/m3 0.73 mg/m3 0.47 mg/m3

Key Reference: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation Median Lethal 

Concentration (LC50) 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, estimated 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 BMCL05 for lethality, 22 mg/m3

) 

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: Cn x t = k, where n = 1.6 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 

3 

4 
OXAMYL 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/m3 8.2 mg/m3 5.3 mg/m3 2.2 mg/m3 1.4 mg/m3

Key Reference: Kelly, D.P. 2001. Oxamyl (DPX-D1410) Technical (98%w/w): Inhalation Median Lethal 

Concentration (LC50) 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 acetylcholinesterase activity inhibition; lethality 

Endpoint/Concentration/Rationale: 4-hour BMCL05, 22 mg/m3, threshold for lethality 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 10 

Interspecies: 3, The U.S. EPA (2007b) Office of Pesticide Programs calculated an oxamyl-specific 

inhalation interspecies uncertainty factor of 3 based on modeled values for erythrocyte cholinesterase 

activity inhibition between rats and humans. 

Intraspecies: 3.48, The U.S. EPA (2007b) Office of Pesticide Programs calculated an oxamyl-specific 

inhalation intraspecies uncertainty factor of 3.48 based 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: n value of 1.6 (Cn 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