1 NAC Proposed 1: June 2009

2 

3 

4 

5 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

6 FOR

7 METHOMYL

8 (CAS Reg. No. 16752-77-5) 

9 

10 

11 

12 

13 

14 PROPOSED 

15 

16 

17 
METHOMYL NAC Proposed 1: June 2009/ Page 2 of 35 

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 
METHOMYL NAC Proposed 1: June 2009/ Page 3 of 35 

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 Toxicity .............................................................................................................................9 

8 3.2. Repeat-Exposure Studies...........................................................................................................11 

9 3.3. Neurotoxicity.............................................................................................................................12 

10 3.4. Developmental/Reproductive Toxicity......................................................................................12 

11 3.5. Genotoxicity ..............................................................................................................................13 

12 3.6. Chronic Toxicity/Carcinogenicity .............................................................................................13 

13 3.7. Summary....................................................................................................................................13 

14 4. SPECIAL CONSIDERATIONS ........................................................................................................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-Exposure 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 ....................................................................................................17 

28 6.1. Summary of Human Data Relevant to AEGL-2........................................................................17 

29 6.2. Summary of Animal Data Relevant to AEGL-2........................................................................18 

30 6.3. Derivation of AEGL-2...............................................................................................................18 

31 7. DATA ANALYSIS FOR AEGL-3 ....................................................................................................18 
METHOMYL NAC Proposed 1: June 2009/ Page 4 of 35 

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...............................................................................................................19 

4 8. SUMMARY OF AEGLs....................................................................................................................19 

5 8.1. AEGL Values and Toxicity Endpoints......................................................................................19

6 8.2. Comparison with Other Standards and Guidelines....................................................................20 

7 8.3. Data Adequacy and Research Needs .........................................................................................21 

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

9 APPENDIX A: Derivation of Methomyl AEGLs......................................................................................25 

10 APPENDIX B: Category Graph of AEGL Values and Toxicity Data.......................................................27 

11 APPENDIX C: Benchmark Concentration Calculations ...........................................................................29 

12 APPENDIX D: Derivation Summary for Methomyl AEGLs....................................................................33 
METHOMYL NAC Proposed 1: June 2009/ Page 5 of 35 

1 LIST OF TABLES 

2 S 1. Summary of AEGL Values for Methomyl.........................................................................................................7 

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

4 TABLE 2. Acute Toxicity of Methomyl to Rats Exposed for 4 Hours .................................................................11

5 TABLE 3. Adult Rat and Human BMD10 and BMDL10 Values for Cholinesterase Activity Inhibition with N6 Methyl Carbamate Pesticides (Oral Dosing)..................................................................................................15

7 TABLE 4. AEGL-1 Values for Methomyl ..............................................................................................................17

8 TABLE 5. AEGL-2 Values for Methomyl ..............................................................................................................18

9 TABLE 6. AEGL-3 Values for Methomyl ..............................................................................................................19

10 TABLE 7. Summary of AEGL Values for Methomyl............................................................................................20

11 TABLE 8. Standards and Guidelines for Methomyl .............................................................................................20

12 

13 

14 

15 
METHOMYL NAC Proposed 1: June 2009/ Page 6 of 35 

1 SUMMARY

2 

3 Methomyl (CAS No. 16752-77-5) is a crystalline solid N-methyl carbamate insecticide 

4 with a slightly sulfurous odor. Methomyl is used as an insecticide on field crops such as 

5 vegetables, soybeans, and cotton and on some fruits and ornamentals. Technical methomyl is 

6 commercially available as a solid, dust or granular formulation, and as a water soluble 

7 concentrate. Methomyl is manufactured commercially by the reaction of methyl thiomethyl 

8 oxime with methyl isocyanate. An estimated 2.5 to 3.5 million pounds of active ingredient are 

9 applied annually in the United States. 

10 

11 Methomyl and other carbamate pesticides are neurotoxic in that they are inhibitors of the 

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

13 the biological activity of the neurotransmitter acetylcholine at various nerve endings, results in 

14 sustained stimulation of electrical activity. Depending on concentrations administered, 

15 symptoms following acute exposure of rats to methomyl may include salivation, lacrimation, 

16 gasping and tremors or convulsions. Inhibition of acetylcholinesterase activity is reversible. In 

17 humans, inhibition of erythrocyte acetylcholinesterase activity is used as a biomarker of methyl 

18 carbamate exposure. Based on oral studies, the half-life for methomyl-induced inhibition of 

19 erythrocyte acetylcholinesterase activity in humans is 1.6 hours. No inhalation studies involving 

20 human subjects were located. Given that methyl carbamate pesticides do not have a port of entry 

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

22 acetylcholinesterase activity inhibition levels measured in oral studies with humans and adult 

23 and juvenile rodents are applicable for determination of interspecies and intraspecies uncertainty 

24 factors. Four inhalation rat studies with methomyl administered in different physical forms 

25 provided consistent, concentration-related effects. All exposure durations were for 4 hours. 

26 

27 No studies that adequately reported details of methomyl exposure and effects consistent 

28 with the definition of AEGL-1 were located. Therefore, AEGL-1 values are not recommended. 

29 

30 The lethality study of DuPont (1991) in which methomyl was administered to rats via the 

31 inhalation route shows that methomyl has a steep concentration-response curve. In the absence 

32 of other relevant data, AEGL-2 values for chemicals with a steep concentration-response curve 

33 may be derived by dividing the AEGL-3 values by 3 (NRC 2001). For consistency with the 

34 aerosol study used to derive AEGL-3 values, the AEGL-2 values were derived by dividing the 

35 AEGL-3 values by 3. The AEGL-2 values are supported by the vapor study of DuPont (1966a) 

in which all six rats exposed to 44 mg/m3 36 of methomyl vapor for 4 hours displayed clinical signs 

37 of slight salivation and lacrimation, slight to moderate hyperpnea, and mild dyspnea. 

Application of the same uncertainty factors and time scaling relationship to the 4-hour 44 mg/m3 38 

39 value results in AEGL-2 values similar to those derived by dividing the AEGL-3 by 3 (10-

minute through 8-hour values of 5.9, 5.9, 4.7, 2.9, and 1.5 mg/m3 40 ). 

41 

42 The exposure of rats for 4 hours to a range of aqueous aerosol concentrations that 

43 resulted in lethality at the higher concentrations (DuPont 1991; Panepinto 1991) was chosen as 

44 the key study for derivation of AEGL-3 values. The study used an adequate number of rats of 

45 both sexes and five test concentrations. Mortality in rats inhaling 137, 181, 182, 232, or 326 

mg/m3 46 of an aqueous aerosol of methomyl for 4 hours showed mortality of 0/10, 0/10, 1/10, 

47 6/10, and 7/10, respectively. The benchmark concentration program was used to estimate the 
METHOMYL NAC Proposed 1: June 2009/ Page 7 of 35 

1 threshold for lethality. The benchmark concentration program was run with and without the 

highest value of 326 mg/m3 2 . Omitting the highest value resulted in a better fit of the data to the 

curve. The calculated 4-hour BMCL05 was 157.3 mg/m3

, and the BMC01 was 166.51 mg/m3 3 . 

The BMCL05 was considered the threshold for lethality. The 4-hour 157.3 mg/m3 4 value was 

5 divided by inter- and intraspecies uncertainty factors of 5 and 3.05, respectively, for a total of 15. 

6 The methomyl-specific uncertainty factors were derived by U.S. EPA (2007). The methomyl7 specific interspecies inhalation uncertainty factor of 5 was based on differences in modeled 

8 values for erythrocyte acetylcholinesterase activity inhibition between rats and humans. The 

9 intraspecies uncertainty factor was based on comparative brain acetylcholinesterase activity 

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

uncertainty factor of 3.05 to protect sensitive young. The resulting 4-hour 10.48 mg/m3 11 value 

was time-scaled (Cn 12 x t = k) using the default values of 3 and 1 for longer and shorter exposure 

13 durations, respectively (NRC 2001). 

14 

15 The calculated values are listed in the table below. 

16 

S 1. Summary of AEGL Values for Methomyl

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

AEGLB1 

(Nondisabling) 

Not 

recommended 

Not 

recommended

Not 

recommended

Not 

recommended 

Not 

recommended 

Inadequate data 

AEGLB2 

(Disabling) 

7.0 mg/m3 7.0 mg/m3 5.7 mg/m3 3.3 mg/m3 1.7 mg/m3 AEGL-3 values divided 

by 3 (based on steep 

concentration-response 

curve) 

AEGLB3 

(Lethal) 

21 mg/m3 21 mg/m3 17 mg/m3 10 mg/m3 5.2 mg/m3 Calculated BMCL05 for 

lethality – rat (DuPont 

1991) 

Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 

All values were derived from 4-hour studies. 

17 

18 

19 1. INTRODUCTION

20 

21 Technical methomyl (CAS No. 16752-77-5) is a crystalline solid N-methyl carbamate 

22 insecticide with a slight sulfurous odor. Methomyl is a broad-spectrum insecticide used on 

23 vegetables, soybeans, cotton and other field crops and on some fruits and ornamentals. The 

24 technical material is formulated as a bait/solid, dust, or granular formulation, and as a water 

25 soluble concentrate liquid. Formulated products such as LannateTM contain 90% methomyl (U.S. 

26 EPA 1998; O’Neil 2001 et al.; DuPont 2007). Methomyl is available as wettable powder (25%), 

27 soluble concentrate (200 g/L), and water soluble powder (deVreede et al. 1988). Dilution 

28 instructions are: soluble concentrate, 100-150 mL/100 L water and wettable powder, 80-120 

29 g/100 L water. Products are intended for occupational use only and not for homeowner use. 

30 Methomyl is also a degradate of the pesticide thiodicarb (U.S. EPA 1998). Chemical and 

31 physical properties are listed in Table 1. 

32 

33 Methomyl is manufactured commercially by the reaction of methyl thiomethyl oxime 

34 with methyl isocyanate (HSDB 2009). An estimated 2.5 to 3.5 million pounds of active 

35 ingredient of methomyl are applied annually in the United States (U.S. EPA 1998). 
METHOMYL NAC Proposed 1: June 2009/ Page 8 of 35 

1 

TABLE 1. Chemical and Physical Properties 

Parameter Value Reference 

Synonyms N-[[(Methylamino)carbonyl]oxy] 

ethanimidothioic acid methyl ester; N-

[(methylcarbamoly)oxy]thioacetimidic 

acid methyl ester; S-methyl N-

[(methylcarbamoyl)oxy]thioacetimidate; 

methyl O-(methylcarbamyl)thiol 

acetohydroxamate; Methyl carbamic acid, 

ester with oxime function of 

thiolacetohydroxamic acid, S-methyl 

ester; DuPont 1179; Lannate; Nudrin; 

DPX-X1179; INX-1179 

O’Neil et al. 2001; 

DuPont 2007 

Chemical formula C5H10N2O2S O’Neil et al. 2001 

Molecular weight 162.21 O’Neil et al. 2001 

CAS Reg. No. 16752-77-5 O’Neil et al. 2001 

Physical state crystalline solid O’Neil et al. 2001 

Solubility in water 58 g/L O’Neil et al. 2001 

Vapor pressure 5 x 10-5 torr at 25oC ACGIH 1992 

Vapor density (air =1) No data 

Liquid density (water =1) 1.2946 at 25oC DuPont 2007 

Melting point 78-79oC O’Neil et al. 2001 

Boiling point 136 oC (autodecomposition) DuPont 2007 

Flammability limits in air 0.096 g/L (lower explosive limit) DuPont 2007 

Conversion factors 1 ppm = 6.63 mg/m3

1 mg/m3

 = 0.15 ppm 

Calculated 

2 

3 

4 2. HUMAN TOXICITY DATA 

5 

6 No inhalation studies other than accidental exposures were located. Most of these 

7 accidental exposures lacked information on concentrations. A pilot who was spraying methomyl 

8 and Bravo (chlorothalonil) accidently crashed and died (Driskell et al. 1991). Gas 

9 chromatography/flame ionization analysis of the pilot’s blood revealed a methomyl 

10 concentration of 570 ng/mL of blood. Blood was not analyzed for Bravo. A farmer who died 

11 following several days of application of methomyl in his greenhouse had a blood methomyl 

12 concentration of 1.6 mg/L and 89% blood cholinesterase activity inhibition upon admittance to 

13 the hospital in an unconscious state (Tsatsakis et al. 2001). Death was attributed to inhalation 

14 and dermal exposure as the farmer’s hair and clothes were wet with pesticide and no methomyl 

15 was found in his stomach. An oral lethal dose for humans has been estimated at 12 to 15 mg/kg 

16 (ACGIH 1992). 

17 

18 In a double-blind human oral dosing study, 19 healthy male volunteers, ages 18-40 years 

19 ingested a single oral dose of methomyl formulation (89% a.i.) (McFarlane et al. 1998, reviewed 

20 in U.S. EPA 2005). Five subjects comprised each treated group; there were four control 

21 subjects. Doses of 0, 0.1, 0.2, or 0.3 mg/kg body weight were ingested in capsule form along 

22 with a light breakfast. Clinical symptoms were recorded pre-dose and at set times post-dose. 

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

24 as were clinical chemistry and hematology parameters. One subject in the 0.3 mg/kg group 
METHOMYL NAC Proposed 1: June 2009/ Page 9 of 35 

1 reported a headache at one hour. The only dose-related clinical sign was an increase in saliva in 

2 the 0.3 mg/kg group at 1-hour post dose. Dose-related inhibition of plasma and erythrocyte 

3 cholinesterase activity peaked at 45 minutes post dose. At that time, plasma cholinesterase 

4 activity in the 0.1, 0.2, and 0.3 mg/kg dose groups were -5.6, -11.5, and -21% of baseline. 

5 Respective decreases in erythrocyte cholinesterase activity were -2.5, -20, and -35%. However, 

6 erythrocyte acetylcholinesterase activity in the 0.1 and 0.2 mg/kg groups was inhibited by 19% 

7 (75 minutes post dose) and 28% (90 minutes post dose), respectively. The Human Studies 

8 Review Board (HSRB 2006) reviewed the study and found it met ethical considerations. 

9 

10 3. ANIMAL TOXICITY DATA 

11 

12 Using standard protocols, methomyl has been tested for ocular and dermal irritation in 

13 the rabbit and dermal sensitization with the guinea pig (Kaplan and Sherman 1977; U.S. EPA 

14 1998). In studies summarized by U.S. EPA (1998), methomyl induced transient corneal opacity 

15 of the rabbit eye following instillation of 10 mg, but failed to induce skin irritation or skin 

16 sensitization. A female rabbit treated with 15 mg technical methomyl in the eye died within 20 

17 minutes with typical cholinergic symptoms indicative of neurotoxicity. The oral LD50 in male 

18 and female rats was 20 mg/kg, and the dermal LD50 in rabbits as an aqueous suspension was 

19 >5000 mg/kg (Kaplan and Sherman 1977). 

20 

21 3.1. Acute Toxicity 

22 

23 All inhalation studies were conducted with rats (Table 2). Studies were conducted with 

24 methomyl vapor (one study), dust/powder (one study), or mist/aerosol (three studies). Methomyl 

25 has a low vapor pressure and vapor atmospheres high enough to cause clinical signs are difficult 

26 to sustain. In the vapor study, two groups of six male ChR-CD rats inhaled methomyl vapor at 

nominal concentrations of 36 or 44 mg/m3 27 for 4 hours (DuPont 1966a). The vapor was 

28 generated by passing dry air through a tube of the test material. Exposures were conducted in a 

29 whole-body 16-L chamber. No deaths occurred. Clinical signs during exposure included face30 pawing, slight salivation and lacrimation, hyperemia, hyperpnea, and mild dyspnea in all rats in 

the 44 mg/m3

 group and in one of six rats in the 36 mg/m3 31 group. Mild hyperpnea and 

32 exophthalmos lasted up to 30 minutes post-exposure. No gross effects attributed to exposure 

33 were seen at necropsy. Microscopically, lung and tracheal tissue were similar to those of control 

34 rats in other studies conducted by the same laboratory. The atmospheres were characterized as 

35 one-tenth of the approximate lethal concentration and almost six times the saturated vapor 

pressure of 7 x 10-4 36 mm Hg at 35oC cited in this study. 

37 

 Fifteen male Wistar rats inhaled 9.9 mg/m3 38 methomyl dust/powder for 4 hours in a 0.43 

m3 39 exposure chamber (Ta’naka et al. 1987). The powder concentration was monitored with a 

40 light scattering system. The mass median aerodynamic diameter of the particles was 4.4±2.9 

41 μm. Rats were sacrificed at 0, 1, 2, 4, or 20 hours post-exposure, and erythrocyte and plasma 

42 cholinesterase activities were measured by the Ellman method at each time point. Plasma 

43 acetylcholinesterase activity was inhibited at 0, 1, 2, and 4 hours by approximately 50% (values 

44 read from graph), but had recovered by 20 hours post-exposure. Erythrocyte 

45 acetylcholinesterase activity was either not inhibited or only slightly inhibited depending on 

46 erythrocyte preparation procedures. Erythrocytes were washed three times with isotonic saline 

47 prior to hemolysis. Repeated washing may have removed some of the enzyme from the cell 
METHOMYL NAC Proposed 1: June 2009/ Page 10 of 35 

1 membrane. Histologic findings in major organs were unremarkable. Clinical signs, if present, 

2 were not described. 

3 

4 Groups of five male and five female CrL:CD rats inhaled methomyl mist, nose-only, at 

concentrations of 137, 181, 182, 232, or 326 mg/m3 5 for 4 hours (DuPont 1991; Panepinto 1991). 

6 The study adhered to U.S. EPA’s Good Laboratory Practice (GLP) standards. Purity of the test 

7 material was 97.7%. Atmospheres were generated by suspending the milled solid material at a 

8 concentration of 3% in water and maintaining suspensions with a nebulizer. Aerosol 

9 atmospheres were measured with a gravimetric method. Mass median aerodynamic diameter of 

10 the particles ranged from 1.3 to 3.8 μ. Surviving rats were observed for 14 days post-exposure. 

11 There was a moderate weight loss in most rats during the first two days post-exposure. No rats 

12 died at the two lower concentrations. In these two groups, clinical signs observed during the 

13 first two days post-exposure included diarrhea and stained, ruffled, or wet fur, and discharge 

14 from the eyes or nose, the latter in a few males on days 1, 2, or 3. Mortalities were 1/10, 6/10, 

15 and 7/10 at the three highest concentrations, with mortality comparable between the sexes. 

16 Clinical signs among rats that died included those seen at the lower concentrations and in 

17 addition, abnormal gait, tremors, hyperactivity, hyperreactivity, muscle fasciculations, and 

hunched posture. The calculated 4-hour LC50 was 258 mg/m3 18 . 

19 

20 Groups of six male ChR-CD rats inhaled an aerosol of methomyl, whole-body, for 4 

hours (DuPont 1966b). Concentrations were 250, 300, 350, and 560 mg/m3 21 . The atmospheres 

22 were generated by melting 20 grams of the test material followed by aerosolization of the heated 

23 compound with a nebulizer in a heated air stream. A second unheated air stream carried the 

24 aerosol into a 16-L exposure chamber containing the rats. Aerosol particle size ranged from 1.1-

25 6.8 μ. Gross and histologic examinations were performed on selected rats. No rats died 

following the 4-hour exposure to 250 mg/m3. The approximate LC50 was 300 mg/m3 26 . Clinical 

27 signs observed in dying rats were ptosis, face-pawing, lacrimation and salivation, moderate to 

28 heavy dyspnea, gasping, hyperemia with slight cyanosis, red discharge from the nostrils, and 

29 tremor with mild convulsions followed by terminal convulsions. Similar, but milder signs were 

30 seen at the non-lethal concentrations. Gross effects at necropsy included slight pulmonary 

31 hyperinflation with irregular congestion. 

32 

33 Groups of six male rats (strain not identified) inhaled an aqueous spray mist of 

methomyl, whole-body in a 16 m3 34 chamber for 4 hours (DuPont 1967; Hornberger 1967; 

35 summarized in Kaplan and Sherman 1977). The respirable mist of average mass median 

36 diameter of 3.2-6.3 μ in the different trials was generated with a nebulizer. Atmospheres were 

measured gravimetrically. Concentrations were 97, 130, 333, 420, 540, 600, and 950 mg/m3 37 . 

38 Respective mortality was 0/6, 0/6, 1/6, 2/6, 5/6. 5/6, and 6/6. Clinical signs during the first 

39 minutes of exposure included rapid tremors, irregular breathing, increased grooming, salivation, 

40 and lacrimation. Irregular breathing was observed throughout the exposure. Deaths occurred 

41 only during the first 150 minutes of the 4-hour exposure. Surviving rats were maintained for two 

42 weeks during which time they displayed normal growth. A second study in the same report 

indicated that all six rats exposed head-only to 450 mg/m3 43 generated as non-respirable droplets 

44 >100 μ in size died within 18 minutes. All exposed areas were wet. 

45 

46 

47 
METHOMYL NAC Proposed 1: June 2009/ Page 11 of 35 

TABLE 2. Acute Toxicity of Methomyl in Rats Exposed for 4 Hours 

Concentration 

(mg/m3) Effect or Mortality LC50 (mg/m3) Reference 

Vapor 

36 

44 

No mortality, face-pawing, slight salivation 

and lacrimation hyperemia, hyperpnea, mild 

dyspnea (1 of 6 animals) 

No mortality; above clinical signs in 6 of 6 

rats 

─ DuPont 1966a 

Powder 

9.9 Transient plasma acetylcholinesterase 

activity inhibition (50%); little or no effect 

on erythrocyte acetylcholinesterase activitya

─ Ta’naka et al. 1987 

Mist/Liquid Aerosol 

137 

181 

182 

232 

326 

No mortality; diarrhea, ruffled fur 

No mortality; diarrhea, ruffled fur 

Mortality: 1 of 10 rats; stained fur 

Mortality: 6 of 10 rats; clinical signs 

including tremors in one female (day 1) 

Mortality: 7 of 10 rats; tremors, clinical 

signs including tremors in one male and one 

female (day 1) 

258 DuPont 1991; 

Panepinto 1991 

250 

300 

350 

560 

No mortality 

Mortality: 3 of 6 rats 

Mortality: 6 of 6 rats 

Mortality: 6 of 6 rats 

300 DuPont 1966b 

97 

130 

333 

420 

540 

600 

950 

No mortality 

No mortality 

Mortality of 1 of 6 rats 

Mortality of 2 of 6 rats 

Mortality of 5 of 6 rats 

Mortality of 5 of 6 rats 

Mortality of 6 of 6 rats 

450 DuPont 1967; 

Hornberger 1967 

a 1 The values for erythrocyte cholinesterase activity inhibition are questionable due to repeated washing of the cells. 

2 

3 

4 3.2. Repeat-Exposure Studies

5 

 Ten male Wistar rats inhaled 14.8 mg/m3 6 methomyl powder for 4 hours/day, 5 days/week 

7 for 3 months (Ta’naka et al. 1987). The powder concentration in the chamber was monitored 

8 with a light scattering system. The mass median aerodynamic diameter of the particles was 

9 4.4±2.9 μ. Rats were weighed and sacrificed 4 hours after the last exposure, and erythrocyte and 

10 plasma cholinesterase activity were measured by the Ellman method. Major organs were 

11 weighed and examined microscopically and lungs were analyzed for lipid concentration. No 

12 statistically significant differences were found between the control and exposed groups in body 

13 or organ weights. At 4 hours post-exposure, mean plasma cholinesterase activity was inhibited 

14 by 28% and erythrocyte acetylcholinesterase activity was inhibited by 8%. There were no 

15 histopathologic changes in major organs and no accumulation of lipids in the lungs. The authors 

16 concluded that the effects of methomyl exposure are not cumulative. 

17 
METHOMYL NAC Proposed 1: June 2009/ Page 12 of 35 

1 For comparison to the inhalation route, a repeat exposure dermal study and a repeat 

2 exposure dietary toxicity study are provided. In a 21-day dermal toxicity study with New 

3 Zealand rabbits, the NOAEL was 90 mg/kg/day, the highest dose tested. There were no 

4 mortalities and no toxicologically significant inhibition of plasma, erythrocyte, or brain 

5 cholinesterase activity. In a 90-day feeding study with CD rats, the NOAEL was 6.25 mg/kg/day 

6 (summarized in U.S. EPA 1998), based on lower body weight gain in both sexes and erythroid 

7 hyperplasia in male rats at the next higher dose of 12.5 mg/kg/day. There were no mortalities 

8 and no inhibition of cholinesterase activity. 

9 

10 3.3. Neurotoxicity

11 

12 Acute toxicity studies (see Section 3.1) showed that methomyl is neurotoxic. Although 

no clinical signs were reported in rats inhaling methomyl dust at 9.9 mg/m3 13 for 4 hours (Ta’naka 

et al. 1987), higher concentrations including vapor concentration as low as 36 mg/m3 14 and dust 

aerosols as low as 137 mg/m3 15 induced clinical signs consistent with cholinesterase activity 

16 inhibition (See Section 4.1 for the mode of action of carbamate insecticides). 

17 

18 In a study of gavage administration of methomyl to male Long-Evans rats, motor activity 

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

20 erythrocyte cholinesterase activity inhibition (McDaniel et al. 2007). Doses were 0.10, 0.25, 

21 0.60, 1.25, or 2.50 mg/kg. Cholinesterase activity inhibition and related decreased motor activity 

22 were dose dependent above 0.10 mg/kg. Brain and erythrocyte cholinesterase activity were 

23 similarly inhibited at the higher doses. At 2.50 mg/kg, vertical motor activity was 20% of the 

24 control value and brain and erythrocyte cholinesterase were 50-60% of the control value. 

25 

26 3.4. Developmental/Reproductive Toxicity

27 

28 No inhalation studies were conducted that addressed the developmental/reproductive 

29 toxicity of methomyl. Reproductive and developmental toxicity studies that used the oral route 

30 of administration were reviewed by Kaplan and Sherman (1977) and U.S. EPA (1998). In 

31 developmental studies, pregnant CD rats were administered methomyl at concentrations of 0, 

32 4.9, 9.4, or 33.9 mg/kg/day on gestation days 6-19. The maternal LOAEL was 33.9 mg/kg/day 

33 based on decreased body weight gain and food consumption; the developmental NOAEL was 

34 33.9 mg/kg/day. In a recent study, pregnant New Zealand rabbits were administered 0, 2, 6, or 

35 16 mg/kg/day by stomach tube on gestation days 7-19. The maternal LOAEL was 16 mg/kg/day 

36 based on mortality and clinical signs indicating neurotoxicity. The developmental NOAEL was 

37 16 mg/kg/day, the highest dose tested. In a two-generation reproduction study, the F0 generation 

38 of Sprague-Dawley rats was fed methomyl at dose levels of 0, 3.75, 30, or 60 mg/kg/day. The F1

39 offspring were treated at the same dosage. The parental NOAEL and LOAEL were 3.75 and 30 

40 mg/kg/day, respectively; the LOAEL was based on decreased body weight and food 

41 consumption and altered hematology parameters. The offspring NOAEL and LOAEL were also 

42 3.75 and 30 mg/kg/day, based on a decrease in mean number of pups and decreased pup body 

43 weight at 30 mg/kg/day. The U.S. EPA concluded that the data provided no indication of 

44 increased sensitivity of rats or rabbits to in utero or postnatal exposure to methomyl. There was 

45 no assessment of functional development. 

46 
METHOMYL NAC Proposed 1: June 2009/ Page 13 of 35 

1 3.5. Genotoxicity

2 

3 Methomyl has been tested in a range of in vitro genotoxicity assays (IPCS 1996; 2001; U.S. 

4 EPA 1998; HSDB 2009). Most assays were conducted both with and without metabolic 

5 activation. Methomyl did not cause mutagenicity or primary DNA damage in bacterial or 

6 mammalian cells. Assay results were negative for point mutations in Salmonella typhimurium

7 (TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli WP2 uvrA. Results were 

8 negative for DNA damage in E. coli; Bacillus subtilis; Saccharomyces cerevisiae; human lung 

9 fibroblasts, lymphocytes, and skin cells; and rat hepatocytes. Methomyl assay results were 

10 negative in gene mutation tests with Chinese hamster V79 and ovary cells and in a sister11 chromatid exchange assay in human lymphocytes. Methomyl showed cytogenetic potential in 

12 human lymphocytes in vitro as indicated by an increase in micronuclei and chromosomal 

13 aberrations. 

14 

15 3.6. Chronic Toxicity/Carcinogenicity 

16 

17 Methomyl was tested for chronic toxicity and carcinogenicity in two-year dietary studies 

18 with male and female beagle dogs, male and female CD rats, and male and female CD-1 mice 

19 (Kaplan and Sherman 1977; ACGIH 1992; U.S. EPA 1998). No increased tumor incidence 

20 occurred in any study. Dogs fed ≥10 mg/kg/day showed microscopic changes in the kidneys, 

21 spleen and liver. The NOAEL for dogs was 5 mg/kg/day. The NOAEL for rats was 5 

22 mg/kg/day based on depressed body weight gain in both sexes at higher doses. No effects were 

23 observed in mice at the highest dose, 120 mg/kg/day. The U.S. EPA has classified methomyl in 

24 Group E, not likely to be carcinogenic to humans via relevant routes of exposure. The 

25 carcinogenicity of methomyl has not been evaluated by the International Agency for Research on 

26 Cancer. 

27 

28 3.7. Summary

29 

30 Acute inhalation lethality studies were conducted with the rat. The 4-hour LC50 values 

for rats ranged from 258 to 510 mg/m3 31 for methomyl suspended as a mist or aerosol (DuPont 

32 1966b ; Kaplan and Sherman 1977; DuPont 1991). During exposure rats showed signs 

33 indicative of cholinesterase activity inhibition. In another study, clinical signs were either not 

described or not observed in rats exposed to 9.9 mg/m3 34 of dust for 4 hours (Ta’naka et al. 1987). 

35 Plasma cholinesterase activity inhibition was greater (50%) following the acute exposure than 

following exposure to 14.8 mg/m3 36 for 4 hours/day, 5 days/week for 3 months (28%). A study 

with the saturated vapor of methomyl (36 or 44 mg/m3 37 ) did not attain concentrations high 

38 enough to elicit mortality, although clinical signs indicative of acetylcholinesterase activity 

39 inhibition were evident (DuPont 1966a). 

40 

41 No evidence of teratogenicity was observed in either rats or rabbits treated in the diet 

42 with methomyl (rats, up to 60 mg/kg/day) even in the presence of maternal toxicity. A range of 

43 genotoxicity assays provided mostly negative results. In 2-year feeding studies with the dog, rat, 

44 and mouse at concentrations that approached toxic, there was no evidence of a tumorigenic 

45 response. 

46 
METHOMYL NAC Proposed 1: June 2009/ Page 14 of 35 

1 4. SPECIAL CONSIDERATIONS

2 4.1. Metabolism and Disposition

3 

4 Inhalation studies with methomyl that addressed metabolism were not located. Oral 

5 absorption is near complete (95-98%) and most of the compound is eliminated in 24 hours 

6 (ACGIH 1992). The N-methyl carbamates do not have a port of entry effect, are expected to be 

7 rapidly absorbed, and do not require activation (U.S. EPA 2007). Unlike some organophosphate 

8 pesticides that are metabolized by A-esterases which show great inter-individual variation, the 

9 biotransformation of the carbamate pesticides does not involve these esterases. Metabolism was 

10 outlined following oral dosing of male and female CD rats (Harvey et al. 1973) and male and 

11 female Sprague-Dawley rats (Jaglan and Arnold 1984) with radiolabeled methomyl. Syn12 methomyl, the form of methomyl that is produced and sold, is hydrolyzed at the ester linkage to 

13 give rise to an oxime which is metabolized to CO2. Approximately 34-54% of the label is 

14 eliminated in the urine as the oxime or conjugates of the oxime and 20-39% is eliminated as 

15 expired CO2 and acetonitrile (ratio 2:1). The major urinary metabolite was the mercapturic acid 

16 derivative of methomyl (IPCS 1996). Acetonitrile is likely formed following partial conversion 

17 of the syn-isomer to the anti-isomer prior to hydrolysis at the ester linkage. Two to three percent 

18 of the radiolabel is eliminated in the feces, and less than 10% remains in the carcass. 

19 

20 Metabolism pathways in the monkey were similar to those of the rat, but with differences 

21 in the percent of metabolites formed (IPCS 1996). Following administration of an oral dose of 5 

22 mg/kg body weight, expired air contained 32-38% of the dose as CO2 and 4-7% of the dose as 

23 acetonitrile. Eighteen metabolites were characterized in the urine, with no metabolite 

24 representing more than 4% of the dose. Most of the metabolites were eliminated in the first 24 

25 hours post-exposure. 

26 

27 In addition to hydrolysis of the carbamate ester linkage, several oxidation and reduction 

28 reactions involving cytochrome P450-related monooxygenases can form polar metabolites 

29 (Costa 2008). Methyl and N-methyl side chains undergo hydroxylation, followed by conjugation 

30 with glucuronide or sulfate derivatives. 

31 

32 4.2. Mechanism of Toxicity

33 

34 Methomyl is an N-methyl carbamate insecticide. The mode of action of carbamate 

35 pesticides involves cholinesterase inhibition (U.S. EPA 2007; Costa 2008). Carbamic acid esters 

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

37 responsible for the destruction and termination of the biological activity of the neurotransmitter 

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

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

40 stimulation of the muscarinic receptors of the parasympathetic autonomic nervous system are 

41 manifest as increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, diarrhea, 

42 urination, and bradycardia. Stimulation of the parasympathetic junctions of the autonomic 

43 nervous system as well as the junctions between nerves and muscles cause tachycardia, 

44 hypertension, muscle fasciculation, tremors, muscle weakness, and flaccid paralysis. Signs and 

45 symptoms resulting from effects on the central nervous system include restlessness, emotional 

46 lability, ataxia, lethargy, mental confusion, loss of memory, generalized weakness, convulsion, 

47 cyanosis, and coma. 
METHOMYL NAC Proposed 1: June 2009/ Page 15 of 35 

1 

2 Inhibition of acetylcholinesterase activity is transient and reversible because there is 

3 rapid reactivation of the carbamylated enzyme in the presence of water. Maximum inhibition 

4 typically occurs between 15 and 45 minutes after exposure. Carbamates also inhibit 

5 butylcholinesterase, the primary form found in blood plasma. The toxicological significance of 

6 butylcholinesterase activity inhibition is unknown. Acetylcholinesterase is the primary form of 

7 cholinesterase found in erythrocytes and is present at neuromuscular and nerve-nerve junctions. 

8 A review of studies submitted to U.S. EPA (2007) for pesticide registration shows that clinical 

9 signs and behavioral effects are not evident below 10% cholinesterase activity inhibition, but in 

10 most studies a 10% brain cholinesterase activity inhibition can be reliably detected. Due to 

11 human variability, it is difficult to measure erythrocyte acetylcholinesterase activity inhibition of 

12 <20% (U.S. EPA 2000). At greater than 30% erythrocyte or 50% plasma cholinesterase activity 

13 inhibition, workers are withdrawn from pesticide application areas (U.S. EPA 2000). 

14 

15 In adult Long-Evans rats dosed orally with 3 mg/kg methomyl, brain and erythrocyte 

16 acetylcholinesterase activity were approximately 47 and 33% of control values, respectively, at 

17 0.5 hours; activity in both compartments returned to the level of control values by 4 hours post18 dosing (Padilla et al. 2007). 

19 

20 4.3. Structure-Activity Relationships

21 

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

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

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

25 cholinesterase undergo fairly rapid hydrolysis; the carbamylated (inhibited) enzyme is 

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

27 

28 Information is available on the relative oral toxicity of three N-methyl carbamate 

29 pesticides (HSRB 2006; U.S. EPA 2007). The endpoints were brain and erythrocyte 

30 cholinesterase activity inhibition in the rat and erythrocyte cholinesterase activity inhibition in 

31 humans. Raw data consisting of erythrocyte cholinesterase activity inhibition were not provided 

32 for all three chemicals, but relative toxicity can be derived from the benchmark doses (BMD10

33 and BMDL10) calculated by U.S. EPA (2007) from a range of oral doses (Table 3). For 

34 methomyl and oxamyl, rat data on brain and erythrocyte cholinesterase activity are presented by 

35 McDaniel et al. (2007). If oxamyl is assigned a relative oral potency factor of 1, then the oral 

36 potencies of aldicarb and methomyl are 4 and 0.67, respectively (U.S. EPA 2007). 

37 

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

Rat Human 

Brain Erythrocyte Erythrocyte 

Chemical Benchmark 

Dose (mg/kg) 

Half-life 

(h) 

Benchmark 

Dose (mg/kg) 

Half-life 

(h) 

Benchmark 

Dose (mg/kg) 

Half-life 

(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 0.9 BMD10: 0.278 0.8 BMD10: 0.083 2.4 
METHOMYL NAC Proposed 1: June 2009/ Page 16 of 35 

BMDL10: 0.127 BMDL10: 0.158 BMDL10: 0.068 

1 Benchmark dose data for brain cholinesterase activity for aldicarb and oxamyl are the average of male and female rat 

2 values. 

3 The BMDL10 for 10% brain cholinesterase activity inhibition was used as the point of departure for U.S. EPA (2007) 

4 risk assessment. 

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

6 

7 4.4. Other Relevant Information

8 4.4.1. Species Variability

9 

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

11 with the rat, mouse, and dog showed little difference in toxicity among the species. The extent 

12 of hydrolysis of carbamate ester insecticides varies between species, ranging from 30 to 95%, 

13 and is chemical specific (Costa 2008). Baseline erythrocyte acetylcholinesterase activity is 

14 higher in humans than in other species (Ellin 1981). The U.S. EPA Office of Pesticide Programs 

15 (U.S. EPA 2007) compared the toxicity (endpoint cholinesterase activity inhibition) of three N16 methyl carbamate pesticides, oxamyl, methomyl, and aldicarb, using oral dosing in humans and 

17 in juvenile and adult rats. Most data were available for oxamyl which was used as the index 

18 chemical. Benchmark doses were calculated for brain and erythrocyte acetylcholinesterase 

19 activity inhibition in juvenile and adult rats and erythrocyte cholinesterase activity inhibition in 

20 humans. Based on the comparative erythrocyte acetylcholinesterase activity inhibition for equal 

21 oral doses in adult rats and humans, the U.S. EPA calculated a chemical-specific interspecies 

22 uncertainty factor of 5 for methomyl. For most of these chemicals, the interspecies uncertainty 

23 factor is used for all routes of exposure. The half-lives for regeneration of erythrocyte 

24 acetylcholinesterase activity in rats and humans were 0.8 and 1.6 hours, respectively. 

25 

26 4.4.2. Susceptible Populations

27 

28 Humans are known to vary by gender, age, and genetic make-up in their sensitivity to 

29 cholinesterase inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 

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

31 activity units) by a factor of 1.6 (Herz et al. 1975). The U.S. EPA (2007) identified infants and 

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

33 pesticides. In so doing, they evaluated the relative sensitivity of juvenile and adult rats to N34 methyl carbamate pesticides including methomyl. Developmental neurotoxicity studies showed 

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

36 acetylcholinesterase activity inhibition in utero. Therefore, intraspecies uncertainty factors were 

37 based on relative juvenile and adult rat sensitivity to brain acetylcholinesterase activity 

38 inhibition. Based on comparative brain acetylcholinesterase activity inhibition in methomyl39 treated post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated a Food Quality 

40 Protection Act (FQPA) uncertainty factor for children of 3.05 . This uncertainty factor 

41 corresponds to an AEGL intraspecies uncertainty factor. The estimated half-life for recovery of 

42 brain acetylcholinesterase activity in juvenile rats was 0.4 hours (U.S. EPA 2007). 

43 

44 4.4.3. Concentration-Exposure Duration Relationship

45 

46 No data were available for evaluating the relationship between ambient concentrations of 

47 methomyl and exposure duration for a single endpoint. The concentration-time relationship for a 
METHOMYL NAC Proposed 1: June 2009/ Page 17 of 35 

1 single endpoint for many irritant and systemically acting vapors and gases may be described by 

Cn 2 x t = k. In the absence of empirical data, the time scaling factors of n = 3 and n = 1 are used 

3 to scale to shorter and longer exposure durations respectively (NRC 2001). 

4 

5 4.4.4. Concurrent Exposure Issues

6 

7 Dermal absorption may occur, but toxicity is low compared to inhalation exposure as 

8 indicated by a dermal LD50 of >5000 mg/kg in rabbits (Kaplan and Sherman 1977). Concurrent 

9 exposure to other N-methyl carbamates in proportion to their potency indicates that they follow a 

10 dose-additive model of brain cholinesterase inhibition (Padilla et al. 2006; U.S. EPA 2007). 

11 

12 5. DATA ANALYSIS FOR AEGL-1

13 5.1. Summary of Human Data Relevant to AEGL-1

14 

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

16 monitoring data were presented by U.S. EPA (1998). 

17 

18 5.2. Summary of Animal Data Relevant to AEGL-1

19 

20 Ta’naka et al. (1987) exposed rats to an atmosphere of methomyl powder for 4 hours. 

Rats inhaling 9.9 mg/m3 21 for 4 hours showed plasma cholinesterase activity inhibited by 

22 approximately 50%, but erythrocyte acetylcholinesterase activity was reported as either not 

23 affected or only slightly inhibited. No clinical signs were described. In the human oral dosing 

24 study (McFarlane et al. 1998), plasma cholinesterase activity inhibition was accompanied by a 

25 corresponding inhibition in erythrocyte acetylcholinesterase activity. These results raise some 

26 questions about the rat inhalation study in which plasma but not erythrocyte activity was 

27 significantly inhibited. 

28 

29 5.3. Derivation of AEGL-1

30 

The study of Ta’naka et al. (1987) in which rats inhaled 9.9 mg/m3 31 methomyl powder 

32 for 4 hours was considered inadequate for derivation of AEGL-1 values. The study did not 

33 appear to accurately report erythrocyte acetylcholinesterase activity inhibition. In addition, the 

34 presence or absence of clinical signs was not clearly stated. No other studies addressed effects 

35 defined by the AEGL-1. Therefore, AEGL-1 values are not recommended. 

36 

TABLE 4. AEGL-1 Values for Methomyl

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

Not recommended Not recommended Not recommended Not recommended Not recommended 

37 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect.

38 

39 6. DATA ANALYSIS FOR AEGL-2

40 6.1. Summary of Human Data Relevant to AEGL-2

41 

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

43 

44 
METHOMYL NAC Proposed 1: June 2009/ Page 18 of 35 

1 6.2. Summary of Animal Data Relevant to AEGL-2

2 

3 No inhalation studies with methomyl dust that addressed effects consistent with the 

4 definition of the AEGL-2 were reported in the available literature. One of six rats exposed to a 

nominal concentration of 36 mg/m3 5 of methomyl vapor showed mild signs of cholinesterase 

6 activity inhibition. These signs included face-pawing, slight salivation and slight lacrimation 

and mild dyspnea (DuPont 1966a). At the higher concentration of 44 mg/m3 7 , all six rats showed 

8 these clinical signs, and the signs were more severe, but recovery within 14 days was complete. 

9 Higher vapor atmospheres could not be attained. 

10 

11 The lethality study with an aqueous aerosol of methomyl (DuPont 1991; Panepinto 

1991), showed a steep concentration-response relationship. No mortality occurred at 181 mg/m3 12 , 

but six of ten rats died at 232 mg/m3 13 . 

14 

15 6.3. Derivation of AEGL-2

16 

17 Lethality data show that methomyl has a steep concentration-response curve. In the 

18 absence of other relevant data, AEGL-2 values for chemicals with a steep concentration19 response curve may be derived by dividing the AEGL-3 values by 3 (NRC 2001). For 

20 consistency with the study used to derive AEGL-3 values, the AEGL-2 values were derived by 

21 dividing the AEGL-3 values by 3. Values are summarized in Table 5, calculations are in 

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

23 B. 

24 

TABLE 5. AEGL-2 Values for Methomyl

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

7.0 mg/m3 7.0 mg/m3 5.7 mg/m3 3.3 mg/m3 1.7 mg/m3

25 

26 The vapor study of DuPont (1966a) supports the values derived by dividing the AEGL-3 

by 3. Inhalation exposure of rats to of 44 mg/m3 27 over a period of 4 hours induced clinical signs 

consistent with the definition of the AEGL-2. Dividing the 4-hour 44 mg/m3 28 value by 15 (see 

29 Section 7.3 for discussion of uncertainty factors) and time-scaling using the default values of 3 

30 and 1 for shorter and longer exposure durations, respectively, results in 10-minute through 8-

hour values of 5.9, 5.9, 4.7, 2.9, and 1.5 mg/m3 31 . These values are comparable with the derived 

32 values shown in Table 5. The fact that no rats died at the lowest tested concentration of 137 

mg/m3 33 in the study by DuPont (1991) also supports the AEGL-2 values. 

34 

35 7. DATA ANALYSIS FOR AEGL-3

36 7.1. Summary of Human Data Relevant to AEGL-3

37 

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

39 the available literature. 

40 

41 7.2. Summary of Animal Data Relevant to AEGL-3

42 

43 Three studies with methomyl as a mist or liquid aerosol addressed lethality in the rat. All 

studies were for 4 hours. Four-hour LC50 values were 258 mg/m3 44 (DuPont 1991; Panepinto 
METHOMYL NAC Proposed 1: June 2009/ Page 19 of 35 

1991), 300 mg/m3 (DuPont 1966b), and 450 mg/m3 1 (DuPont 1967; Hornberger 1967). Although 

2 performed at different times, the three studies by DuPont give consistent values. The 1991 GLP 

3 study by DuPont used both sexes of rats and provides good dose-response information. There 

4 was little difference in toxicity between the sexes. Tested concentrations were 137, 181, 182, 

232, and 326 mg/m3 5 and respective mortalities were 0/10, 0/10, 1/10, 6/10, and 7/10 rats. 

6 

7 7.3. Derivation of AEGL-3

8 

9 The GLP study of DuPont 1991 (Panepinto 1991) was chosen as the basis for AEGL-3 

10 values. In that study, male and female rats inhaled an aerosol of methomyl generated by 

11 suspending the solid in water. Benchmark concentrations were calculated (1) using all of the 

data and (2) deleting the highest value of 326 mg/m3 12 . Omitting the highest value provided a 

13 better mathematical fit of the data to a curve. With omission of the highest value, the calculated 

4-hour BMCL05 is 157.26 mg/m3, and the BMC01 is 166.51 mg/m3 14 (Appendix C). The 

15 NAC/AEGL committee generally uses the BMCL05 as the estimate at which lethality is not 

16 likely to be observed (NRC 2001). 

17 

The 157.3 mg/m3 18 value was divided by inter- and intraspecies uncertainty factors of 5 

19 and 3.05, respectively, for a total of 15. The U.S. EPA (2007) derived an interspecies 

20 uncertainty factor of 5 for methomyl based on differences in modeled red blood cell values for 

21 acetylcholinesterase activity inhibition between the rat and humans (See section 4.4.1). Based 

22 on comparative brain cholinesterase activity inhibition in post-natal day 11 juvenile rats and 

23 adult rats, the U.S. EPA calculated an uncertainty factor of 3.05 to protect sensitive young (See 

24 section 4.4.2). The combined uncertainty factor is 15. The data set with application of an 

25 uncertainty factor that protects sensitive juveniles provides a reasonable estimate of lethality. 

The resulting value of 10.49 mg/m3

 (157.3 mg/m3/15) was time-scaled (Cn 26 x t = k) from the 4-

27 hour data point to 1 hour and to 30 minutes using the default n value of 3 and to the 8-hour 

28 exposure duration using the default value of 1 (NRC 2001). Because the key study was 4 hours, 

29 the 10-minute value was set equal to the 30-minute value. Values are summarized in Table 6, 

30 calculations are in Appendix A, and a category graph of the toxicity data in relation to AEGL 

31 values is in Appendix B. 

32 

TABLE 6. AEGL-3 Values for Methomyl 

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

21 mg/m3 21 mg/m3 17 mg/m3 10 mg/m3 5.2 mg/m3

33 

The BMCL05 value of 157.3 mg/m3 34 is higher than the lowest concentration causing no 

mortality (137 mg/m3

) in the key study. No deaths occurred at 181 mg/m3 35 , but this value is 

virtually identical with the 182 mg/m3 36 value that resulted in the death of 1 of 10 rats. 

37 

38 8. SUMMARY OF AEGLs

39 8.1. AEGL Values and Toxicity Endpoints 

40 

41 AEGL values are summarized in Table 7. Derivations are summarized in Appendix D. 

42 

43 

44 
METHOMYL NAC Proposed 1: June 2009/ Page 20 of 35 

TABLE 7. Summary of AEGL Values for Methomyl

Exposure Duration

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

AEGL-1 

(Nondisabling) 

Not 

recommended 

Not 

recommended 

Not 

recommended 

Not 

recommended 

Not 

recommended 

AEGL-2 

(Disabling) 

7.0 mg/m3 7.0 mg/m3 5.7 mg/m3 3.3 mg/m3 1.7 mg/m3

AEGL-3 

(Lethal) 

21 mg/m3 21 mg/m3 17 mg/m3 10 mg/m3 5.2 mg/m3

1 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect.

2 

3 8.2. Comparison with Other Standards and Guidelines 

4 

5 Standards and guidelines for methomyl are listed in Table 8. The American Conference of 

6 Government Industrial Hygienists (ACGIH 1992) Threshold Limit Value-Time Weighted 

Average (TLV-TWA) is 2.5 mg/m3 7 . Although far less than the no-adverse-effect-level identified 

8 in animal studies, this value incorporates a margin of safety in view of doses associated with 

9 human poisoning. This 8-hour value is for healthy adults, whereas the lower AEGL-2 value of 

1.7 mg/m3 10 is protective of infants and children. The ACGIH has derived a Biological Exposure 

11 Index (BEI) for workers based on erythrocyte cholinesterase activity of acetylcholinesterase 

12 inhibiting chemicals (ACGIH 2008). The value is ≤70% of an individual’s baseline red blood 

13 cell acetylcholinesterase activity. 

14 

TABLE 8. Standards and Guidelines for Methomyl

Exposure Duration

Guideline 10 min 30 min 1 h 4 h 8 h 

AEGL-1 Not 

recommended 

Not 

recommended 

Not 

recommended 

Not 

recommended 

Not 

recommended 

AEGL-2 7.0 mg/m3 7.0 mg/m3 5.7 mg/m3 3.3 mg/m3 1.7 mg/m3

AEGL-3 21 mg/m3 21 mg/m3 17 mg/m3 10 mg/m3 5.2 mg/m3

ERPG-1 (AIHA)a ─ 

ERPG-2 (AIHA) ─ 

ERPG-3 (AIHA) ─

IDLH 

(NIOSH)b 

─ 

REL-TWA 

(NIOSH)c 

 2.5 mg/m3

OSHA PEL 

(NIOSH)d

 ─

TLV-TWA 

(ACGIH)e 

 2.5 mg/m3

MAK (Germany)f ─

MAC (The 

Netherlands)g

 2.5 mg/m3

15 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 

16 a 17 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association 

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

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

20 perceiving a clearly defined objectionable odor. 

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

22 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 
METHOMYL NAC Proposed 1: June 2009/ Page 21 of 35 

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

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

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

4 b 5 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) 

6 represents the maximum concentration from which one could escape within 30 minutes without any escape7 impairing symptoms, or any irreversible health effects. 

8 c 9 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 

10 Time Weighted Average) (NIOSH 2008) is defined analogous to the ACGIH-TLV-TWA. 

11 d 12 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 

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

14 hours/day, 40 hours/week. 

15 e 16 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 

17 Time Weighted Average) (ACGIH 1992) is the time-weighted average concentration for a normal 8-hour workday 

18 and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse 

19 effect. 

20 

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

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

23 

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

25 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined similar to 

26 the ACGIH TLV. 

27 

28 8.3. Data Adequacy and Research Needs

29 

30 Methomyl has a low vapor pressure and no suitable studies involving inhalation exposure 

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

32 addressed effects consistent with cholinesterase activity inhibition. Five inhalation studies with 

33 rats as the test species were sufficient for derivation of two AEGL levels for five timepoints. 

34 Studies involving comparisons of cholinesterase activity inhibition between juvenile and adult 

35 rats and between rats and humans addressed chemical-specific uncertainty factors. Metabolism 

36 pathways and mode of action are well understood. 

37 

38 9. REFERENCES

39 

40 ACGIH (American Conference of Government and Industrial Hygienists). 1992. Methomyl. 

41 Documentation of the Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: 

42 ACGIH. 

43 

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

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

46 Biological Exposure Indices. Cincinnati, OH: ACGIH. 

47 

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

Science of Poisons. 7th 49 Ed. New York: McGraw-Hill. 

50 

51 de Vreede, J.A.F., D.H. Brouwer, H. Stevenson, and J.J. van Hemmen. 1998. Exposure and risk 

52 estimation for pesticides in high-volume spraying. Ann. Occup. Hyg. 42:151-157. 

53 
METHOMYL NAC Proposed 1: June 2009/ Page 22 of 35 

1 Driskell, W.J., D.F. Groce, R.H. Hill, Jr., and M.M. Birky. 1991. Methomyl in the blood of a pilot who 

2 crashed during aerial spraying. J. Anal. Toxicol. 15:339-340. 

3 

4 DuPont. 1966a. Acute Inhalation Toxicity. Haskell Laboratory Report No. 214-66. Haskell Laboratory 

5 for Toxicology and Industrial Medicine, Newark, DE. 

6 

7 DuPont. 1966b. Acute Inhalation Toxicity (Progress Report). Haskell Laboratory Report No. 73-66. 

8 Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. 

9 

10 DuPont. 1967. Acute Inhalation Toxicity Study of Aqueous Spray Mist. Haskell Laboratory Report No. 

11 171-67. Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. (Same as 

12 Hornberger 1967). 

13 

14 DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell Laboratory 

15 Report No. 678-91. Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. 

16 (Same as Panepinto 1991). 

17 

18 DuPont. 2007. Material Safety Data Sheet: DuPont Lannate SP Insecticide. Available online, Dupont 

19 Chemical Co. 

20 

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

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

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

24 Information Center, AD A1013364. 

25 

26 Harvey, J., A.G. Jeinek and H. Sherman. 1973. Metabolism of methomyl in the rat. Agric. Food Chem. 

27 21:769-775. 

28 

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

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

31 

32 Hornberger, C.S. 1967. Acute Inhalation Toxicity Study of Aqueous Spray Mist. Haskell Laboratory 

33 Report No. 171-67. Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. 

34 (Same as DuPont 1967). 

35 

36 HSDB (Hazardous Substances Data Bank). 2009. Methomyl. National Library of Medicine. Available 

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

38 

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

40 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 

41 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting42 materials/apr-4-6-2006-public-meeting/april2006mtgfinalreport62606.pdf. 

43 

44 IPCS (International Program on Chemical Safety). 1996. Environmental Health Criteria 178: Methomyl. 

45 World Health Organization. Available online: 

46 http://www.inchem.org/documents/ehc/ehc/ehc178.htm. 

47 

48 IPCS (International Program on Chemical Safety). 2001. Pesticide residues in food – 2001- 

49 Toxicological Evaluations: Methomyl (addendum). Joint Meeting on Pesticide Residues. World 

50 Health Organization. Available online: 

51 http://www.inchem.org/documents/jmpr/jmpmono/2001pr08.htm. 

52 
METHOMYL NAC Proposed 1: June 2009/ Page 23 of 35 

1 Jaglan, P.S. and T.S. Arnold. 1984. Metabolism of the insecticidal carbamate methyl N-[[[[[(1,1-

2 dimethylethyl)(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2yl)-

3 amino]thio]methylamino]carbonyl]oxy]ethanimidothioate in rats. J. Agric. Food Chem. 32:618-622. 

4 

5 Kaplan, A.M. and H. Sherman. 1977. Toxicity studies with methyl N6 [[(methylamino)carbonyl]oxy]ethanimidothioate. Toxicol. Appl. Pharmacol. 40:1-17. 

7 

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

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

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

11 

12 McFarlane, P., J.B. Sanderson, and S. Freestone. 1998. A randomized double blind ascending oral dose 

13 study with methomyl to establish a no adverse effect level. Inveresk Clinical Research, Riccarton, 

14 Edinburgh, Scotland. HLO-1998-00969. (Summarized in U.S. EPA 2005, MRID 44721401). 

15 

16 NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to 

17 Chemical Hazards. Available online: http://www.cdc.gov/niosh/npgd0455.html. 

18 

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

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

21 

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

23 NJ: Merck & Co., Inc., p. 6015. 

24 

25 Padilla, S., W. Setzer, R.S. Marshall, D. Hunter, P. Phillips, K. McDaniel, V.C. Moser, and A. Lowit. 

26 2006. A dose-response study of the toxicity of a mixture of 7 N-methyl carbamates in adult, male 

rats. Presented at the 45th 27 Annual Meeting of the Society of Toxicology, San Diego, CA. 

28 

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

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

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

32 

33 Panepinto, A.S. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell 

34 Laboratory Report No. 678-91. Haskell Laboratory for Toxicology and Industrial Medicine, Newark, 

35 DE. (Same as DuPont 1991). 

36 

37 SDU Uitgevers. 2000. Nationale MAC List. Under the auspices of the Ministry of Social Affairs and 

38 Employment. The Netherlands: The Hague. 

39 

40 Ta’naka, I., H. Igisu, J. Haratake, S. Cho, K. Mori, K. Fujishiro, N. Inoue, A. Horie, and T. Akiyama. 

41 1987. Cumulative toxicity potential of methomyl aerosol by repeated inhalation. Am. Ind. Hyg. J. 

42 48:330-334. 

43 

44 Tsatsakis, A.M., G.K. Bertsias, I.N. Mammas, I. Stiakakis, and D.B. Georgopoulos. 2001. Acute fatal 

45 poisoning by methomyl caused by inhalation and transdermal absorption. Bull. Environ. Contam. 

46 Toxicol. 66:415-420. 

47 

48 U.S. EPA (U.S. Environmental Protection Agency). 1991. Methomyl. In Drinking Water Health 

49 Advisory: Pesticides. Chelsea, MI: Lewis Publishers, pp. 521-539. 

50 

51 U.S. EPA (U.S. Environmental Protection Agency). 1998. Reregistration Eligibility Decision (RED) for 

52 Methomyl. Available online: www.epa.gov/pesticides/reregistration/REDs/methomyl_red.pdf. 
METHOMYL NAC Proposed 1: June 2009/ Page 24 of 35 

1 

2 U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticide Programs Science Policy 

3 on The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and 

4 Carbamate Pesticides. Washington, DC: U.S. Environmental Protection Agency. Available online: 

5 http://www.epa.gov/pesticides/trac/science/cholin.pdf. 

6 

7 U.S. EPA (U.S. Environmental Protection Agency). 2005. Data Evaluation Record: Methomyl/90301 

8 (MRID 44721401). Available online: Regulations.gov/methomyl 90301. Citation: McFarlane et al. 

9 1998. A randomized double blind ascending oral dose study with methomyl. Inveresk Clinical 

10 Research, Riccarton, Edinburgh, Scotland. Laboratory Project ID: HLO-1998-00969, November 30, 

11 1998. 

12 

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

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

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

16 

17 
METHOMYL NAC Proposed 1: June 2009/ Page 25 of 35 

1 

2 APPENDIX A: Derivation of Methomyl AEGLs 

3 

4 Derivation of AEGL-1 Values 

5 

6 No human inhalation studies or adequately reported animal studies were located that 

7 reported effects consistent with the definition of the AEGL-1. Therefore, AEGL-1 values are not 

8 recommended. 

9 

10 

11 Derivation of AEGL-2 Values

12 

13 Key Study: DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in 

14 Rats. Haskell Laboratory Report No. 678-91. Haskell Laboratory for 

15 Toxicology and Industrial Medicine, Newark, DE. (same as Panepinto 1991). 

16 

17 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentration-response line curve 

18 by the DuPont 1991 data justifies deriving AEGL-2 values by dividing the 

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

20 

21 Time scaling See AEGL-3 derivation, next page 

22 

23 Uncertainty factors: Total uncertainty factor: 15 (See AEGL-3 derivation, next page). 

24 

25 Calculations: AEGL-3 values divided by 3 

26 

10-min AEGL-2: C = 21 mg/m3/3 = 7.0 mg/m3 27 

28 

30-min AEGL-2: C = 21 mg/m3/3 = 7.0 mg/m3 29 

30 

1-h AEGL-2: C = 17 mg/m3/3 = 5.7 mg/m3 31 

32 

4-h AEGL-2: C = 10 mg/m3/3 = 3.3 mg/m3 33 

34 

8-h AEGL-2: C = 5.2 mg/m3/3 = 1.7 mg/m3 35 

36 
METHOMYL NAC Proposed 1: June 2009/ Page 26 of 35 

1 

2 Derivation of AEGL-3 Values

3 

4 Key Study: DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in 

5 Rats. Haskell Laboratory Report No. 678-91. Haskell Laboratory for 

6 Toxicology and Industrial Medicine, Newark, DE (same as Panepinto 1991). 

7 

Toxicity endpoint: Threshold for lethality in rats at the BMCL05 of 157.264 mg/m3 8 calculated 

9 from the rat lethality data of DuPont (1991) (with omission of the highest 

10 value). 

11 

Time scaling Cn 12 x t = k where n = 3 and 1 for shorter and longer exposure durations, 

13 respectively 

14 

15 Uncertainty factors: Total uncertainty factor: 15 

16 Interspecies: 5 – Based on differences in modeled values for red blood cell 

17 cholinesterase activity inhibition between rats and humans following oral 

18 ingestion of methomyl (U.S. EPA 2007). 

19 Intraspecies: 3.05 – Based on comparative brain acetylcholinesterase activity 

20 inhibition in post-natal day 11 juvenile rats and adult rats exposed to 

21 methomyl (U.S. EPA 2007). 

22 

23 Modifying factor: None applied 

24 

Calculations: (157.264 mg/m3/15)3 x 240 minutes = (27.66 x 104) mg/m3 25 •min 

 (157.264 mg/m3/15)1 x 240 minutes = 2516.22 mg/m3 26 •min 

27 

10-min AEGL-3: C = 21 mg/m3 28 (set equal to the 30-minute value because of the long study 

29 duration) 

30 

30-min AEGL-3: C = 3√(27.66 x 104 mg/m3•min) = 21 mg/m3 31 

32 

1-h AEGL-3: C = 3√(27.66 x 104 mg/m3•min) = 17 mg/m3 33 

34 

4-h AEGL-3: C = 157.264 mg/m3/15 = 10 mg/m3 35 

36 

8-h AEGL-3: C = 2516.22 mg/m3•min/480 min = 5.2 mg/m3 37 

38 
METHOMYL NAC Proposed 1: June 2009/ Page 27 of 35 

1 APPENDIX B: 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

Category Graph - Animal Data

Methomyl

AEGL-3

AEGL-2

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 NR 10 AEGL 

 NAC/AEGL-1 NR 30 AEGL 

 NAC/AEGL-1 NR 60 AEGL 

 NAC/AEGL-1 NR 240 AEGL 

 NAC/AEGL-1 NR 480 AEGL 

 

 NAC/AEGL-2 7.0 10 AEGL 

 NAC/AEGL-2 7.0 30 AEGL 

 NAC/AEGL-2 5.7 60 AEGL 

 NAC/AEGL-2 3.3 240 AEGL 

 NAC/AEGL-2 1.7 480 AEGL 

 

 NAC/AEGL-3 21 10 AEGL 

 NAC/AEGL-3 21 30 AEGL 

 NAC/AEGL-3 17 60 AEGL 

 NAC/AEGL-3 10 240 AEGL 

 NAC/AEGL-3 5.2 480 AEGL 
METHOMYL NAC Proposed 1: June 2009/ Page 28 of 35 

 

 Ta’naka et al. 1987 rat 9.9 240 0 (clinical signs either absent 

or not described) 

 DuPont 1966a rat 36 240 1 (slight lacrimation, 

salivation, mild dyspnea in 1 

of 6 rats) 

 rat 44 240 1 (slight lacrimation, 

salivation, mild dyspnea in 6 

of 6 rats) 

 DuPont 1966b rat 250 240 2 (lacrimation, salivation, mild 

to moderate dyspnea, tremor, 

convulsions) 

 rat 300 240 SL (death of 3 of 6 rats) 

 rat 350 240 3 (death of 6 of 6 rats) 

 rat 560 240 3 (death of 6 of 6 rats) 

 DuPont 1967; 

 Hornberger 1967 

 rat 97 240 2 (tremors, lacrimation, 

salivation) 

 rat 130 240 2 (tremors, lacrimation, 

salivation) 

 rat 333 240 SL (death of 1 of 6 rats) 

 rat 420 240 SL (death of 2 of 6 rats) 

 rat 540 240 SL (death of 5 of 6 rats) 

 rat 600 240 SL (death of 5 of 6 rats) 

 rat 950 240 3 (death of 6 of 6 rats) 

 DuPont 1991 rat 137 240 2 (diarrhea, ruffled fur) 

 rat 181 240 2 (diarrhea, ruffled fur) 

 rat 182 240 SL (death of 1 of 10 rats)) 

 rat 232 240 SL (death of 6 of 10 rats) 

 rat 326 240 SL (death of 7 of 10 rats) 

Atmospheres of methomyl include powder (Ta’naka et al. 1987), vapor (DuPont 1966a), and mist or liquid 

aerosol (DuPont 1966b; 1967; 1991). 

NR = not recommended. Absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is 

without effect.
METHOMYL NAC Proposed 1: June 2009/ Page 29 of 35 

1 APPENDIX C: Benchmark Concentration Calculations 

2 

3 Calculation of BMCL05

4 Rat lethality data (DuPont 1991; Panepinto 1991) 

5 =============================================================== 

6 Probit Model. (Version: 2.8; Date: 02/20/2007) 

7 Input Data File: C:\BMDS\UNSAVED1.(d) 

8 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 

9 Thu Apr 23 09:12:05 2009 

10 =============================================================== 

11 

12 BMDS MODEL RUN 

13 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

14 The form of the probability function is: 

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

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

17 

18 Dependent variable = COLUMN3 

19 Independent variable = COLUMN1 

20 Slope parameter is not restricted 

21 

22 Total number of observations = 5 

23 Total number of records with missing values = 0 

24 Maximum number of iterations = 250 

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

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

27 

28 User has chosen the log transformed model 

29 

30 Default Initial (and Specified) Parameter Values 

31 Background = 0 

32 intercept = -19.7475 

33 slope = 3.59092 

34 

35 Asymptotic Correlation Matrix of Parameter Estimates 

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

37 have been specified by the user, and do not appear in the correlation matrix ) 

38 

39 intercept slope 

40 intercept 1 -1 

41 slope -1 1 

42 

43 Parameter Estimates 

44 

45 95.0% Wald Confidence Interval 

46 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

47 background 0 NA 
METHOMYL NAC Proposed 1: June 2009/ Page 30 of 35 

1 intercept -42.1724 13.4943 -68.6207 -15.7242 

2 slope 7.78999 2.52426 2.84253 12.7374 

3 

4 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 

5 has no standard error. 

6 

7 Analysis of Deviance Table 

8 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

9 Full model -9.98095 5 

10 Fitted model -10.6556 2 1.34926 3 0.7175 

11 Reduced model -20.2482 1 20.5345 4 0.0003916 

12 AIC: 25.3112 

13 

14 

15 Goodness of Fit 

16 Scaled 

17 Dose Est._Prob. Expected Observed Size Residual 

18 ------------------------------------------------------------------------ 

19 0.0000 0.0000 0.000 0 10 0.000 

20 137.0000 0.0001 0.001 0 10 -0.025 

21 181.0000 0.0468 0.468 0 10 -0.701 

22 182.0000 0.0512 0.512 1 10 0.700 

23 232.0000 0.6016 6.016 6 10 -0.011 

24 Chi^2 = 0.98 d.f. = 3 P-value = 0.8055 

25 

26 Benchmark Dose Computation 

27 Specified effect = 0.05 

28 Risk Type = Extra risk 

29 Confidence level = 0.95 

30 BMC05 = 181.73 

31 BMCL05 = 157.264 

32 

0

0.2

0.4

0.6

0.8

0 50 100 150 200

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

09:12 04/23 2009

BMDL BMD

 

Probit

BMD Lower Bound

33 
METHOMYL NAC Proposed 1: June 2009/ Page 31 of 35 

1 Calculation of BMCL01

2 Rat lethality data (DuPont 1991; Panepinto 1991) 

3 ==============================================================

4 Probit Model. (Version: 2.8; Date: 02/20/2007) 

5 Input Data File: C:\BMDS\UNSAVED1.(d) 

6 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 

7 Thu Apr 23 09:21:15 2009 

8 ============================================================== 

9 

10 BMDS MODEL RUN 

11 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

12 

13 The form of the probability function is: 

14 P[response] = Background + (1-Background) * 

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

16 distribution function 

17 

18 Dependent variable = COLUMN3 

19 Independent variable = COLUMN1 

20 Slope parameter is not restricted 

21 

22 Total number of observations = 5 

23 Total number of records with missing values = 0 

24 Maximum number of iterations = 250 

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

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

27 

28 User has chosen the log transformed model 

29 

30 Default Initial (and Specified) Parameter Values 

31 Background = 0 

32 Intercept = -19.7475 

33 Slope = 3.59092 

34 

35 Asymptotic Correlation Matrix of Parameter Estimates 

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

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

38 

39 intercept slope 

40 intercept 1 -1 

41 slope -1 1 

42 

43 Parameter Estimates 

44 95.0% Wald Confidence Interval 

45 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

46 background 0 NA 

47 intercept -42.1724 13.4943 -68.6207 -15.7242 
METHOMYL NAC Proposed 1: June 2009/ Page 32 of 35 

1 slope 7.78999 2.52426 2.84253 12.7374 

2 

3 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and 

4 thus has no standard error. 

5 

6 Analysis of Deviance Table 

7 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

8 Full model -9.98095 5 

9 Fitted model -10.6556 2 1.34926 3 0.7175 

10 Reduced model -20.2482 1 20.5345 4 0.0003916 

11 AIC: 25.3112 

12 

13 Goodness of Fit 

14 Scaled 

15 Dose Est._Prob. Expected Observed Size Residual 

16 ------------------------------------------------------------------------ 

17 0.0000 0.0000 0.000 0 10 0.000 

18 137.0000 0.0001 0.001 0 10 -0.025 

19 181.0000 0.0468 0.468 0 10 -0.701 

20 182.0000 0.0512 0.512 1 10 0.700 

21 232.0000 0.6016 6.016 6 10 -0.011 

22 

23 Chi^2 = 0.98 d.f. = 3 P-value = 0.8055 

24 

25 Benchmark Dose Computation 

26 Specified effect = 0.01 

27 Risk Type = Extra risk 

28 Confidence level = 0.95 

29 BMC01 = 166.508 

30 BMCL01 = 133.852 

31 

0

0.2

0.4

0.6

0.8

0 50 100 150 200

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

09:21 04/23 2009

BMDL BMD

 

Probit

BMD Lower Bound

32 

33 
METHOMYL NAC Proposed 1: June 2009/ Page 33 of 35 

1 

2 APPENDIX D: Derivation Summary for Methomyl AEGLs 

3 Acute Exposure Guideline Levels for Methomyl 

4 (CAS Reg. No. 16752-77-5) 

5 

AEGL-1 VALUES

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

Not recommended Not recommended Not recommended Not recommended Not recommended 

Key Reference: Insufficient data 

Test Species/Strain/Sex/Number: 

Exposure Route/Concentration/Duration: 

Effects: 

Endpoint/Concentration/Rationale: 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 

Interspecies: 

Intraspecies: 

Modifying Factor: 

Animal to Human Dosimetric Adjustment: 

Time Scaling: 

Data Adequacy: 

6 Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 

7 

8 
METHOMYL NAC Proposed 1: June 2009/ Page 34 of 35 

1 

AEGL-2 VALUES

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

7.0 mg/m3 7.0 mg/m3 5.7 mg/m3 3.3 mg/m3 1.7 mg/m3

Key Reference: DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell 

Laboratory Report No. 678-91. Haskell Laboratory for Toxicology and Industrial Medicine, 

Newark, DE. 

Test Species/Strain/Number: Rat/CrL-CD/6 males per group 

Exposure Route/Concentration/Duration: Inhalation/137, 181, 182, 232, and 326 mg/m3/4 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 in the key AEGL-3 study (NRC 2001). 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 15 (See AEGL-3 summary) 

Interspecies: 

Intraspecies:: 

Modifying Factor: None applied 

Animal to Human Dosimetric Adjustment: Not applicable 

Time Scaling: See AEGL-3 summary 

Data Adequacy: Four studies performed in the same laboratory at different times provided consistent, 

concentration-related results, regardless of the physical state of the test material. The values are supported by 

the 4-hour vapor study of DuPont 1966a in which rats inhaling 44 mg/m3

 for 4 hours exhibited clinical signs 

consistent with the definition of the AEGL-2. 

2 

3 

4 
METHOMYL NAC Proposed 1: June 2009/ Page 35 of 35 

1 

AEGL-3 VALUES

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

21 mg/m3 21 mg/m3 17 mg/m3 10 mg/m3 5.2 mg/m3

Key References: DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell 

Laboratory Report No. 678-91. Haskell Laboratory for Toxicology and Industrial Medicine, Newark, 

DE. 

Test Species/Strain/Number: Rat/Crl-CD/groups of 5 male and 5 female 

Exposure Route/Concentration/Duration: Inhalation/137, 181, 182, 232, or 326 mg/m3 liquid aerosol/ 4 

hours 

Effect: Concentration-related clinical signs and mortality 

Endpoint/Concentration/Rationale: Threshold for lethality, BMCL05 calculated using the benchmark dose 

computer program (highest data point omitted for better curve fitting). 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 15 

Interspecies: 5, Based on differences in modeled values for red blood cell cholinesterase activity 

inhibition between rats and humans following oral ingestion of methomyl (U.S. EPA 2007). 

Intraspecies: 3.05, Based on comparative brain acetylcholinesterase activity inhibition in post-natal day 11 

juvenile rats and adult rats exposed to methomyl (U.S. EPA 2007). 

Modifying Factor: None applied 

Animal to Human Dosimetric Adjustment: Not applicable 

Time Scaling: Cn x t = k where n = 3 and 1 for shorter and longer exposure durations, respectively (NRC 2001) 

Data Adequacy: Four studies performed in the same laboratory but at different times provided consistent, 

concentration-related results, regardless of the physical state of the test material. 

2